Compounds as antagonists or inverse agonists at opioid receptors

ABSTRACT

Novel compounds which are antagonists or inverse agonists at one or more of the opioid receptors, pharmaceutical compositions containing them, to processes for their preparation.

This application is filed pursuant to 35 U.S.C. §371 as a U.S. NationalPhase Application of International Application No. PCT/US2007/075422filed Aug. 8, 2007, which claims priority from U.S. 60/821,845 filedAug. 9, 2006.

FIELD OF THE INVENTION

This invention relates to novel compounds which are antagonists orinverse agonists at one or more of the opioid receptors, topharmaceutical compositions containing them, to processes for theirpreparation, and to their use in therapy.

BACKGROUND OF THE INVENTION

Obesity is a medical condition that is reaching epidemic proportionsamong humans throughout the world. It is a condition that is associatedwith other diseases or conditions that disrupt life and lifestyles.Obesity is recognized as a serious risk factor for other diseases and/orconditions such as diabetes, hypertension, and arteriosclerosis. It isalso known that increased body weight due to obesity can place a burdenon joints, such as knee joints, causing arthritis, pain, and stiffness.

Because overeating and obesity have become such a problem, manyindividuals are interested in weight reduction and/or maintaining ahealthy body weight.

The ability to bind antagonistically to opioid receptors has beensuggested to be useful for treatment of many other diseases orconditions not related to obesity including drug and/or substanceaddiction, depression, opiate overdose, irritable bowel syndrome,schizophrenia, compulsive disorders, septic shock, nausea, vomiting, andstroke. This ability may be useful for the treatment of obesity as well.It has been suggested that the opioid receptors may play a role incontrol of food intake and food selection. (See, for example, Bodnar, R.J., in Peptides, 25, (2004), p. 697.) Antagonists or inverse agonists ofthe opioid receptors have been shown to reduce body weight in obeserats.

There is, therefore, an ongoing need for new opioid antagonists for thetreatment of obesity, diseases and/or conditions associated withobesity, as well as the above-mentioned non-obesity related diseasesand/or conditions.

SUMMARY OF THE INVENTION

The present invention provides a compound of Formula I or Formula Ia,

a salt, a solvate, or physiologically functional derivative thereofwherein:

ring A is selected from the group consisting of aryl, 5-memberedheteroaryl, and 6-membered heteroaryl, with the proviso that in FormulaI when (i) ring A is pyridyl, (ii) ring B is phenyl, and (iii) E is inthe meta position relative to the bond joining ring A to ring B, thebond joining D to ring B is in the para position relative to the bondjoining ring A to ring B and in Formula Ia, ring A is attached to thetetrahydroisoquinolyl ring at carbon 6 or carbon 7;

ring B is selected from the group consisting of aryl, 5-memberedheteroaryl, and 6-membered heteroaryl;

D is —CH₂—, —O—, or —CH(CH₃)—, with the proviso that D is not attachedto ring B at the atom adjacent to the bond joining rings A and B;

E is selected from the group consisting of —C(O)NH₂, —C(O)NHC₁₋₃alkyl,—C(O)NH(C₁₋₃alkyl)aryl, —NHC(O)C₁₋₃alkyl, 5-membered heterocycle,6-membered heterocycle, 5-membered heteroaryl, and 6-memberedheteroaryl, with the proviso that in Formula I E is not attached to theatom adjacent to the bond joining rings A and B;

R¹ and R² are selected independently from the group consisting of —F,—Cl, —Br, —OH, —CN, —C₁₋₃alkyl, —OC₁₋₃alkyl, —C₁₋₃-fluoroalkyl,—OC₁₋₃-fluoroalkyl; m and n are each independently 0, 1, or 2;

J is a bond or a C₁₋₄alkylene;

R³ is selected from the group consisting of —H, C₁₋₁₂alkyl,C₃₋₁₀cycloalkyl, alkoxycarbonyl, arylalkyl, heterocyclyl,heterocyclylalkyl, heteroarylalkyl, cycloalkenyl, C₂₋₁₂-fluoroalkyl, andheteroalkyl;

R⁴ is selected from the group consisting of C₃₋₁₂alkyl, C₃₋₁₀cycloalkyl,arylalkyl, heterocyclyl, heterocyclylalkyl, heteroarylalkyl,cycloalkenyl, C₃₋₁₂-fluoroalkyl, and heteroalkyl; or

R³ and R⁴ may be joined to form a substituted or unsubstituted 5-7membered ring.

The present invention also provides a pharmaceutical compositioncomprising a compound of Formula I or Formula Ia, a salt, solvate, orphysiologically functional derivative thereof and one or moreexcipients.

And the present invention further provides a method of treatmentcomprising the administering to a mammal, particularly a human, apharmaceutical composition comprising (i) a compound of Formula I orFormula Ia, a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof and (ii) at least oneexcipient or carrier, wherein said treatment is for a disease orcondition selected from the group consisting of obesity, diabetes,hypertension, depression, anxiety, drug addiction, substance addiction,or a combination thereof. Preferably the disease or condition isobesity.

There is further provided processes for making compounds of Formula I orFormula Ia, salts, solvates, and physiologically functional derivativesthereof.

DETAILED DESCRIPTION OF THE INVENTION

In Formulae I and Ia, ring A is selected from the group consisting ofaryl, 5-membered heteroaryl, and 6-membered heteroaryl, with the provisothat in Formula I when (i) ring A is pyridyl, (ii) ring B is phenyl, and(iii) E is in the meta position relative to the bond joining ring A toring B, the bond joining D to ring B is in the para position relative tothe bond joining ring A to ring B. Preferably in Formulae I and Ia, ringA is selected from the group consisting of phenyl, thiophenyl, furanyl,oxazolyl, and pyridyl. Of these, preferably ring A is phenyl or pyridyl;most preferably ring A is phenyl. In Formula Ia ring A is attached tothe tetrahydroisoquinolyl ring either through carbon 6 or carbon 7.

Ring B of Formula I is selected from the group consisting aryl,5-membered heteroaryl, and 6-membered heteroaryl. Preferably in FormulaI, ring B is selected from the group consisting of phenyl, thiophenyl,furanyl, and pyridyl. Of these, preferably ring B is phenyl or pyridyl;most preferably ring B is phenyl.

In one embodiment of Formula I, ring A and ring B are both selected fromthe group consisting of phenyl and pyridyl. In Formula I, it is furtherpreferred that ring A and ring B both be phenyl. In a preferredembodiment of Formula I, ring A and ring B are both phenyl and ring B issubstituted one or two times with a halogen such as fluoro or chloro.

In Formula I, D is —CH₂—, —O—, or —CH(CH₃)—, with the proviso that D isnot attached to ring B at the atom adjacent to the bond that joins ringA to ring B. That is, D is not attached to ring B at the ortho positionto the bond that joins ring A to ring B. Preferably in Formula I, D is—CH₂— or —O—.

E of Formulae I and Ia is selected from the group consisting of—C(O)NH₂, —C(O)NHC₁₋₃alkyl, —C(O)NH(C₁₋₃alkyl)aryl, —NHC(O)C₁₋₃alkyl,5-membered heterocycle, 6-membered heterocycle, 5-membered heteroaryl,and 6-membered heteroaryl, with the proviso that E is not attached tothe carbon atom adjacent (i.e., “ortho” position) to the bond joiningrings A and B. Preferably, in Formula I and Formula Ia, E is selectedfrom the group consisting of —C(O)NH₂, imidazolidinyl,imidazolidinedionyl, imidazoyl, imidazolinonyl, triazolyl,triazolinonyl, pyridyl and their tautomers. Most preferably in Formula Iand Formula Ia, E is C(O)NH₂ or triazolyl.

In Formulae I and Ia, R¹ and R² are selected independently from thegroup consisting of —H, —F, —Cl, —Br, —OH, —CN, —C₁₋₃alkyl, —OC₁₋₃alkyl,—C₁₋₃fluoroalkyl, —OC₁₋₃fluoroalkyl. Preferably, R¹ and R² are selectedindependently from the group consisting of —F, —Cl, —CH₃, —CF₃, and—OCH₃. In [R¹]_(n), and [R²]_(m), m and n are each independently 0, 1,or 2.

J in Formula I is a bond or a C₁₋₄alkylene. Preferably, in Formula I, Dis —CH₂— and J is a bond or C₁₋₂alkylene. In one embodiment of FormulaI, when D is —CH₂— then J is a bond or C₁₋₂alkylene. Also, preferably,in Formula I, when D is —O— then J is C₂₋₃alkylene.

In Formula I, R³ is selected from the group consisting of —H,C₁₋₁₂alkyl, C₃₋₁₀cycloalkyl, alkoxycarbonyl, arylalkyl, heterocyclyl,heterocycloalkyl, heteroarylalkyl, cycloalkenyl, C₂₋₁₂fluoroalkyl, andheteroalkyl. R³ can be substituted or unsubstituted.

R⁴ of Formulae I and Ia is selected from the group consisting ofC₃₋₁₂alkyl, C₃₋₁₀cycloalkyl, arylalkyl, heterocyclyl, heterocycloalkyl,heteroarylalkyl, cycloalkenyl, C₃₋₁₂fluoroalkyl, and heteroalkyl. R⁴ canbe substituted or unsubstituted. Preferably, in Formula I, R³ is —H.Preferably, in both Formula I and Formula Ia, R⁴ is selected from thegroup consisting of arylmethyl, arylethyl, heteroarylmethyl,heteroarylethyl, C₄₋₁₀alkyl, cycloalkenyl, cycloalkyl,heterocyclylmethyl, and heterocyclylethyl; such as, but not limited to3-fluorophenylethyl, 3-fluorobenzyl, 2-trifluoromethylbenzyl,2-trifluoromethoxybenzyl, 4-trifluoromethylbenzyl, 4-fluorobenzyl,3-methoxyphenylethyl, 3-thiophenylmethyl, 2-thiophenylethyl,4,4-dimethylcyclohexyl, 3,3-dimethylcyclohexyl, 2-indanyl,5-cyano-2-indanyl, 5-methoxy-2-indanyl, 5-fluoro-2-indanyl,4-fluoro-2-indanyl, 4-methoxy-2-indanyl, 4-methoxy-2-indanyl,4,8-difluoro-2-indanyl, 5,6-difluoro-2-indanyl, 5,6-dimethoxy-2-indanyl,2-methyl-2-indanyl, cyclohexylmethyl, cyclohexylethyl,4,4-difluorocyclohexyl, 1-cyclohexenylmethyl, 1-cyclohexenylethyl,cyclooctyl, cycloheptylmethyl, 3-methylbutyl, adamantyl,morpholinoethyl, piperidinylethyl, 4-tert-butylcyclohexyl,3,3,5,5-tetramethylcyclohexyl, 3,5-difluorobenzyl,3,5-difluorophenylethyl, 2-diphenylmethyl, methoxyethyl,dimethylaminoethyl, 3-pyridinylethyl, 3-pyridinylmethyl, andphenyloxyethyl. Of these, preferably R⁴ is selected from among the groupconsisting of 2-indanyl, 5-fluoro-2-indanyl, 4,4-dimethylcyclohexyl,cyclohexylethyl, cyclohexylmethyl, 2-thiophenylethyl,3-fluorophenylethyl, 3-methylbutyl, and 4,4-difluorocyclohexyl.

Or, in Formula I, R³ and R⁴ may be joined to form a substituted orunsubstituted 5-7 membered ring, including rings such as, but notlimited to piperidinyl, piperizinyl, morpholinyl, azepinyl,tetrahydroisoquinolinyl, dihydroindolyl, and pyrrolidinyl.

Particularly preferred compounds of Formula I are selected from thegroup consisting of4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3-biphenylcarboxamide;4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylcarboxamide;N-{[3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine;4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2-fluoro-3-biphenylcarboxamide;4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2-methyl-3-biphenylcarboxamide;4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2′-(trifluoromethyl)-3-biphenylcarboxamide;3′-fluoro-4′-({[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3-biphenylcarboxamide;1-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-2,4-imidazolidinedione;N-{[3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-4,4-dimethylcyclohexanamine;N-{[3,5-difluoro-3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine;N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-4,4-dimethylcyclohexanamine;N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine;and2′-chloro-4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3-biphenylcarboxamide,including their salts, solvates, and physiologically functionalderivatives. The preferred salts of these named compounds are a citrate,phosphate, or hydrochloride salt (mono- and di-). Tautomers of thesecompounds and their salts are also preferred.

The most preferred compound isN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amineor a salt thereof. A citrate, phosphate or mono- or di-hydrochloridesalt ofN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amineis especially preferred.

In Formula Ia ring A is attached to the tetrahydroisoquinolyl ringeither through carbon 6 or carbon 7, and E, R¹, R², and R⁴ are asdescribed for Formula I. The preferred point of attachment of ring A tothe tetrahydroisoquinolyl ring is through carbon 6 in Formula Ia.

There is provided a pharmaceutical composition comprising (i) a compoundof Formula I or Formula Ia, a pharmaceutically acceptable salt, solvate,or physiologically functional derivative thereof and (ii) at least onecarrier (also referred to as an excipient or diluent), preferably apharmaceutically acceptable carrier.

Further, there is provided a method of treatment (including prophylaxis)comprising the administering to a mammal, especially a human, apharmaceutical composition comprising (i) a compound of Formula I orFormula Ia, a pharmaceutically acceptable salt, solvate, orphysiologically functional derivative thereof and (ii) at least onecarrier (excipient or diluent). There also is provided a method oftreatment (including prophylaxis) comprising the administering to amammal, especially a human, a compound of Formula I or Formula Ia, apharmaceutically acceptable salt, solvate, or physiologically functionalderivative thereof.

One aspect of the present invention includes a compound (salt, solvate,or functional derivative thereof) of the present invention for use as anactive therapeutic substance.

Another aspect of the present invention includes a compound of Formula Ior Formula Ia, a salt, a solvate, or a functional derivative thereof foruse in the treatment (including prophylaxis) of obesity, diabetes,hypertension, depression (major and/or bipolar), anxiety, drugaddiction, and/or substance addiction. Of these conditions/diseases,obesity is preferred.

Still another aspect of the present invention includes the use of acompound of Formula I or Formula Ia, a salt, a solvate, or a functionalderivative thereof in the manufacture of a medicament for use in thetreatment (including prophylaxis) of obesity, diabetes, hypertension,depression (major and/or bipolar), anxiety, drug addiction, and/orsubstance addiction. Of these conditions/diseases, obesity is preferred.

Processes for making the compounds of Formula I or Formula Ia, salts,solvates, and physiologically functional derivatives thereof are alsoset forth.

Terms are used within their accepted meanings. The following definitionsare meant to clarify, but not limit, the terms defined.

As used herein, the term “alkyl” refers to a straight or branched chainalkyl, preferably having from one to twelve carbon atoms, which may beunsubstituted or substituted, with multiple degrees of substitutionincluded within the present invention. Examples of “alkyl” as usedherein include, but are not limited to, methyl, ethyl, propyl,isopropyl, isobutyl, n-butyl, t-butyl, isopentyl, n-pentyl, and thelike, as well as substituted versions thereof.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent alkyl radical, preferably having from one to ten carbonatoms. Alkylene groups as defined herein may be unsubstituted orsubstituted, with multiple degrees of substitution included within thepresent invention. Examples of “alkylene” as used herein include, butare not limited to, methylenyl, ethylenyl, n-propylenyl, n-butylenyl,and the like, as well as substituted versions thereof.

As used herein, the term “cycloalkyl” refers to an unsubstituted orsubstituted mono- or polycyclic non-aromatic saturated ring, whichoptionally includes an alkylene linker through which the cycloalkyl maybe attached. Exemplary “cycloalkyl” groups include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andthe like, as well as unsubstituted and substituted versions thereof. Asused herein, the term “cycloalkyl” includes unsubstituted andsubstituted fused polycyclic hydrocarbon saturated ring and aromaticring system, namely polycyclic hydrocarbons with less than maximumnumber of non-cumulative double bonds, for example where a saturatedhydrocarbon ring (such as a cyclopentyl ring) is fused with an aromaticring (herein “aryl,” such as a benzene ring) to form, for example,groups such as indane.

As used herein, the term “cycloalkenyl” refers to unsubstituted andsubstituted non-aromatic ring containing one or more carbon-to-carbondouble bonds which optionally includes an alkylene linker through whichthe cycloalkenyl may be attached, with multiple degrees of substitutionincluded within the present invention. Exemplary “cycloalkenyl” groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like, as well assubstituted versions thereof.

As used herein, the term “heterocycle” or “heterocyclyl” refers tounsubstituted and substituted mono- or polycyclic non-aromatic ringsystem containing one or more heteroatoms. Preferred heteroatoms includeN, O, and/or S, including N-oxides, sulfur oxides, and dioxides.Preferably the ring is three to twelve-membered and is either fullysaturated or has one or more degrees of unsaturation. Multiple degreesof substitution are included within the present definition. Such ringsmay be optionally fused to one or more of another “heterocyclic” ring(s)or cycloalkyl ring(s). Examples of “heterocyclic” groups include, butare not limited to, tetrahydrofuranyl, pyranyl, 1,4-dioxanyl,1,3-dioxanyl, piperidinyl, pyrrolidinyl, morpholinyl,imidazolidinedionyl, imidazolidinonyl, and their various tautomers.

As used herein, the term “heterocyclylalkyl” refers to a heterocycle, asdefined herein, bonded to an alkyl group, as defined herein.

As used herein, the term “arylalkyl” refers to an aryl group, as definedherein, bonded to an alkyl group, as defined herein.

As used herein, the term “heteroalkyl” refers to an alkyl group, asdefined herein, wherein one or more of the carbon atoms of the alkylgroup are replaced by a heteroatom. Preferred heteroatoms include N, O,and/or S, including N-oxides, sulfur oxides, and sulfur dioxides.

As used herein, the term “aryl” refers to unsubstituted and substitutedbenzene ring. Multiple degrees of substitution are included within thepresent definition. Examples of “aryl” groups include, but are notlimited to, phenyl, benzyl, biphenyl and the like, as well assubstituted derivatives thereof.

As used herein, the term “heteroaryl” refers to unsubstituted andsubstituted monocyclic five to seven membered aromatic ring. Theseheteroaryl rings contain one or more heteroatoms such as nitrogen,sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides, and dioxidesare permissible heteroatom substitutions. Multiple degrees ofsubstitution are included within the present definition. Examples of“heteroaryl” groups used herein include, but should not be limited to,furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl,tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and thelike, as well as substituted versions thereof.

As used herein, the term “heteroarylalkyl” refers to a heteroaryl asdefined herein bonded to an alkyl as defined herein.

As used herein, the term “halogen” refers to fluorine (or fluoro),chlorine (or chloro), bromine (or bromo), or iodine (or iodo).Preferably, each halogen when present is individually either fluorine orchlorine.

As used herein, the term “fluoroalkyl” refers to an alkyl group, asdefined herein, that is substituted with at least one fluorine atom.Examples of branched or straight chained “fluoroalkyl” groups useful inthe present invention include, but are not limited to, methyl, ethyl,propyl, isopropyl, n-butyl, and t-butyl substituted independently withone or more fluorine. The term “fluoroalkyl” should be interpreted toinclude such substituents as perfluoroalkyl groups and the like.

As used herein, the term “alkoxy” refers to the group —OR^(a), whereR^(a) is alkyl as defined above.

As used herein, the term “alkoxycarbonyl” refers to the group—C(O)OR^(a), where R^(a) is alkyl as herein defined

As used herein, the term “nitro” refers to the group —NO₂.

As used herein, the term “cyano” refers to the group —CN.

As used herein, the term “azido” refers to the group —N₃.

As used herein, the term “acyl” refers to the group —C(O)R^(b), whereR^(b) is alkyl, aryl, heteroaryl, or heterocyclyl, as each is definedherein.

As used herein, the term “oxo” refers to the group ═O.

The terms “members” (and variants thereof, e.g., “membered”) in thecontext of heterocyclic, heteroaryl, heteroaromatic, aryl, and aromaticgroups refers to the total atoms, carbons and heteroatoms (e.g., N, O,and S) which form the ring. Thus, an example of a 6-memberedheterocyclic ring is piperidine; an example of a 6-membered heteroarylis pyridine; and an example of a 6-membered aryl ring is benzene.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and event(s) that do not occur.

Also, as used herein throughout the present specification, the phrase“optionally substituted” or variations thereof denote an optionalsubstitution, including multiple degrees of substitution, with one ormore substitutent group. The phrase should not be interpreted asduplicative of the substitutions herein described and depicted.Exemplary optional substituent groups include acyl; alkyl;alkylsulfonyl; alkoxy; alkoxycarbonyl; cyano; halogen; haloalkyl;hydroxy; oxo; nitro; aryl, which may be further substituted with acyl,alkoxy, alkyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, ornitro; heteroaryl, which may be further substituted with acyl, alkoxy,alkyl, alkylsulfonyl, cyano, halogen, haloalkyl, hydroxy, or nitro; or—N(R*)₂; where for each occurrence R* is independently selected fromhydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, aralkyl, heteroaryl,heteroaralkyl, alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, whereeach occurrence of such aryl or heteroaryl may be substituted with oneor more acyl, alkoxy, alkyl, alkenyl, alkylsulfonyl, cyano, halogen,haloalkyl, hydroxy, or nitro, or the two R*s may combine to form a ring,optionally having additional heteroatoms (e.g., N, O, S, etc.),optionally having one or more degrees of unsaturation, and optionallybeing further substituted with acyl, alkoxy, alkyl, halogen, orhaloalkyl.

The compounds of Formula I and Formula Ia may crystallize in more thanone form, a characteristic known as polymorphism, and such polymorphicforms (“polymorphs”) are within the scope of Formula I and Formula Ia.Polymorphism generally can occur as a response to changes intemperature, pressure, or both. Polymorphism can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

Certain compounds of Formula I and Formula Ia may exist instereoisomeric forms (e.g., they may contain one or more asymmetriccarbon atoms or may exhibit cis-trans isomerism). The individualstereoisomers (enantiomers and diastereomers) and mixtures of these areincluded within the scope of the present invention. The presentinvention also covers the individual isomers of the compoundsrepresented by Formula I and Formula Ia as mixtures with isomers thereofin which one or more chiral centers are inverted. Certain compounds ofFormula I and Formula Ia may be prepared as regioisomers. The presentinvention covers both the mixture of regioisomers as well as individualcompounds. Likewise, it is understood that compounds of Formula I andFormula Ia may exist in tautomeric forms other than that shown in theformula and these are also included within the scope of the presentinvention. It is to be understood that the present invention includesall combinations and subsets of the particular groups defined hereinabove. The scope of the present invention includes mixtures ofstereoisomers as well as purified enantiomers orenantiomerically/diastereomerically enriched mixtures. Also includedwithin the scope of the invention are the individual isomers of thecompounds represented by Formula I and Formula Ia, as well as any whollyor partially equilibrated mixtures thereof. The present invention alsoincludes the individual isomers of the compounds represented by theformula as well as mixtures with isomers thereof in which one or morechiral centers are inverted.

Typically the salts of compounds of Formula I and Formula Ia of thepresent invention are pharmaceutically acceptable salts. Saltsencompassed within the term “pharmaceutically acceptable salts” refer tonon-toxic salts of the compounds of this invention. Salts of thecompounds of the present invention may comprise acid addition salts. Ingeneral, the salts are formed from pharmaceutically acceptable inorganicand organic acids. More specific examples of suitable acid salts includemaleic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric,perchloric, fumic, acetic, propionic, succinic, glycolic, formic,lactic, aleic, tartaric, citric, palmoic, malonic, hydroxymaleic,phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic,methansulfonic (mesylate), naphthaliene-2-sulfonic, benzenesulfonic,hydroxynaphthoic, hydroiodic, malic, teroic, tannic, and the like.

Other representative salts include acetate, benzenesulfonate, benzoate,bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate,carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate,esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate,malate, maleate, mandelate, mesylate, methylsulfate, monopotassiummaleate, mucate, napsylate, nitrate, oxalate, pamoate (embonate),palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate,teoclate, tosylate, and valerate salts.

Other salts, which are not pharmaceutically acceptable, may be useful inthe preparation of compounds of this invention and these should beconsidered to form a further aspect of the invention. These salts, suchas oxalic and trifluoroacetic, while not in themselves pharmaceuticallyacceptable, may be useful in the preparation of salts useful asintermediates in obtaining the compounds of the invention and theirpharmaceutically acceptable salts.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound ofFormula I and Formula Ia, or a salt or physiologically functionalderivative thereof) and a solvent. Such solvents, for the purpose of theinvention, should not interfere with the biological activity of thesolute. Non-limiting examples of suitable solvents include, but are notlimited to water, methanol, ethanol, and acetic acid. Preferably thesolvent used is a pharmaceutically acceptable solvent. Most preferablythe solvent used is water and the solvate is a hydrate.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention that, upon administration to a mammal, is capable ofproviding (directly or indirectly) a compound of the present inventionor an active metabolite thereof. Such derivatives, for example, estersand amides, will be clear to those skilled in the art, without undueexperimentation. Reference may be made to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

Processes for preparing pharmaceutically acceptable salts, solvates, andphysiologically functional derivatives of the compounds of Formula I andFormula Ia are generally known in the art. See, for example, Burger'sMedicinal Chemistry and Drug Discovery, 5^(th) Edition, Volume 1:Principles and Practice.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician. The term “therapeuticallyeffective amount” means any amount which, as compared to a correspondingsubject who has not received such amount, results in improved treatment,healing, prevention, or amelioration of a disease, disorder, or sideeffect, or a decrease in the rate of advancement of a disease ordisorder. The term also includes within its scope amounts effective toenhance normal physiological function. For use in therapy,therapeutically effective amounts of a compound of Formula I and FormulaIa, as well as salts, solvates, and physiologically functionalderivatives thereof, may be administered as the raw chemical.Additionally, the active ingredient may be presented as a pharmaceuticalcomposition.

As used herein, the term “treatment” includes prophylaxis and refers toalleviating the specified condition, eliminating or reducing one or moresymptoms of the condition, slowing or eliminating the progression of thecondition, and preventing or delaying the reoccurrence of the conditionin a previously afflicted or diagnosed patient or subject. Prophylaxis(or prevention or delay of disease onset) is typically accomplished byadministering a drug in the same or similar manner as one would to apatient with the developed disease or condition.

Accordingly, the invention further provides pharmaceutical compositions(also referred to herein as “pharmaceutical formulations”) that includeeffective amounts of compounds of the Formula I or Formula Ia, salts,solvates, or physiologically functional derivatives thereof, and one ormore pharmaceutically acceptable excipients (including carriers and/ordiluents). The compounds of Formula I and Formula Ia, salts, solvates,and physiologically functional derivatives thereof, are as hereindescribed. The carrier(s), diluent(s) or excipient(s) must beacceptable, in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient of thepharmaceutical composition.

In accordance with another aspect of the invention there is alsoprovided a process for the preparation of a pharmaceutical formulationincluding admixing a compound of the Formula I or Formula Ia, a salt,solvate, or physiologically functional derivative thereof, with one ormore pharmaceutically acceptable carriers, diluents or excipients.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, thespecies, age, and weight of the recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe route of administration are all factors to be considered. Thetherapeutically effective amount ultimately should be at the discretionof the attendant physician or veterinarian. Regardless, an effectiveamount of a compound of Formula I or Formula Ia (salt, solvate, orderivative thereof) for the treatment of humans suffering from frailty,generally, should be in the range of 0.1 to 100 mg/kg body weight ofrecipient (mammal) per day. More usually the effective amount should bein the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kgadult mammal the actual amount per day would usually be from 70 to 700mg. This amount may be given in a single dose per day or in a number(such as two, three, four, five, or more) of sub-doses per day such thatthe total daily dose is the same. An effective amount of a salt,solvate, or physiologically functional derivative thereof, may bedetermined as a proportion of the effective amount of the compound ofFormula I or Formula Ia (salt, solvate, or derivative thereof) per se.Similar dosages should be appropriate for treatment (includingprophylaxis) of the other conditions referred to herein.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of the Formula I or Formula Ia (alternatively, a salt, solvate,or derivative thereof), depending on the condition being treated, theroute of administration, and the age, weight, and condition of thepatient. Preferred unit dosage formulations are those containing a dailydose or sub-dose, as herein above recited, or an appropriate fractionthereof, of an active ingredient. Such pharmaceutical formulations maybe prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by an oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal, or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s). In the present invention oral routes are preferred.

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions, each with aqueous or non-aqueousliquids; edible foams or whips; or oil-in-water liquid emulsions orwater-in-oil liquid emulsions. For instance, for oral administration inthe form of a tablet or capsule, the active drug component can becombined with an oral, non-toxic pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Generally,powders are prepared by comminuting the compound to a suitable fine sizeand mixing with an appropriate pharmaceutical carrier such as an ediblecarbohydrate, as, for example, starch or mannitol. Flavorings,preservatives, dispersing agents, and coloring agents can also bepresent.

Capsules are made by preparing a powder, liquid, or suspension mixtureand encapsulating with gelatin or some other appropriate shell material.Glidants and lubricants such as colloidal silica, talc, magnesiumstearate, calcium stearate, or solid polyethylene glycol can be added tothe mixture before the encapsulation. A disintegrating or solubilizingagent such as agar-agar, calcium carbonate or sodium carbonate can alsobe added to improve the availability of the medicament when the capsuleis ingested. Moreover, when desired or necessary, suitable binders,lubricants, disintegrating agents, and coloring agents can also beincorporated into the mixture. Examples of suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth, orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, andthe like. Lubricants useful in these dosage forms include, for example,sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride, and the like. Disintegrators include,without limitation, starch, methyl cellulose, agar, bentonite, xanthangum, and the like.

Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant, andpressing into tablets. A powder mixture may be prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove. Optional ingredients include binders such ascarboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone,solution retardants such as paraffin, resorption accelerators such as aquaternary salt, and/or absorption agents such as bentonite, kaolin, ordicalcium phosphate. The powder mixture can be wet-granulated with abinder such as syrup, starch paste, acadia mucilage or solutions ofcellulosic or polymeric materials, and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet-forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material, and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solutions, syrups, and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared, for example, bydissolving the compound in a suitably flavored aqueous solution, whileelixirs are prepared through the use of a non-toxic alcoholic vehicle.Suspensions can be formulated generally by dispersing the compound in anon-toxic vehicle. Solubilizers and emulsifiers such as ethoxylatedisostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives;flavor additives such as peppermint oil, or natural sweeteners,saccharin, or other artificial sweeteners; and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds may also be coupled with soluble polymers as targetabledrug carriers. Such polymers can include polyvinylpyrrolidone (PVP),pyran copolymer, polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug; for example, polylactic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986), incorporated herein by reference as related to such deliverysystems.

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols, or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations may be applied as a topical ointment orcream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles, and mouthwashes.

Pharmaceutical formulations adapted for nasal administration, where thecarrier is a solid, include a coarse powder having a particle size forexample in the range 20 to 500 microns. The powder is administered inthe manner in which snuff is taken, i.e., by rapid inhalation throughthe nasal passage from a container of the powder held close up to thenose. Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered dose pressurized aerosols, nebulizers, orinsufflators.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams, or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats, and solutes that renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders,granules, and tablets.

In addition to the ingredients particularly mentioned above, theformulations may include other agents conventional in the art havingregard to the type of formulation in question. For example, formulationssuitable for oral administration may include flavoring or coloringagents.

The compounds of the present invention, their salts, solvates, orphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents. The compound(s) of FormulaI or Formula Ia and the other pharmaceutically active agent(s) may beadministered together or separately and, when administered separately,administration may occur simultaneously or sequentially, in any order.The amounts of the compound(s) of Formula I or Formula Ia and the otherpharmaceutically active agent(s) and the relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect. The administration in combination of a compound ofFormula I or Formula Ia (salt, solvate, or physiologically functionalderivative thereof) with other treatment compounds or agent may be incombination by administration concomitantly in: (1) a unitarypharmaceutical composition including both compounds; or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one treatment agent is administered first andthe other second or vice versa. Such sequential administration may beclose in time or remote in time.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions and, as such, the compounds of thepresent invention may be used in combination with a variety of othersuitable therapeutic agents useful in the treatment (includingprophylaxis) of obesity and/or associated diseases, disorders, orconditions. More specifically, the present invention includes thetreatment (including prophylaxis) of obesity. Other disorders,conditions, and/or diseases associated with obesity can includediabetes, depression (major and bipolar), anxiety, hypertension, drugand substance addiction, and arteriosclerosis.

One aspect of the present invention comprises a compound of Formula I orFormula Ia (a sat, solvate, or physiologically functional derivativethereof) in combination with at least one other species selected fromthe group consisting of at least one agent or drug for treating obesity,diabetes, hypertension, and arteriosclerosis. In particular, a compoundof Formula I or Formula Ia (a salt, solvate, or physiologicallyfunctional derivative thereof) may be combined with at least one speciesfor the treatment of obesity selected from the group of human ciliaryneurotropic factor, a cannabinoid receptor type 1 (CB-1), antagonist orinverse agonist (such as rimonabant), a neurotransmitter reuptakeinhibitor (such as sibutramine, bupropion, or bupropion HCl,radafaxine), a lipase inhibitor (such as orlistat), a melanocortin 4receptor (MC4R) agonist, a 5-hydroxytryptamine receptor 2c (5-HT2c)agonist, a ghrelin receptor antagonist, a cholecystokinin A receptor(CCK-A) receptor agonist, a neuropeptide Y Y1 receptor (NPY Y1)antagonist, PYY₃₋₃₆ and a peroxisome proliferator-activated recdptor(PPAR) activator.

The compounds of this invention may be made by a variety of methods,including well-known standard synthetic methods. Illustrative generalsynthetic methods are set out below and then specific compounds of theinvention are prepared in the working examples.

Those skilled in the art will recognize if a stereocenter exists incompounds of formula (I). Accordingly, the present invention includesall possible stereoisomers and includes not only racemic compounds butthe individual enantiomers as well. When a compound is desired as asingle enantiomer, such may be obtained by stereospecific synthesis, byresolution of the final product or any convenient intermediate, or bychiral chromatographic methods as are known in the art. Resolution ofthe final product, an intermediate, or a starting material may beaffected by any suitable method known in the art. See, for example,Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L.N. Mander (Wiley-Interscience, 1994), incorporated by reference withregard to stereochemistry.

Processes for Preparing Compounds of Formula I and Formula Ia

In each of the following synthetic descriptions protecting groups forsensitive or reactive groups were employed where necessary in accordancewith general principles of synthetic chemistry. Protecting groups aremanipulated according to standard methods of organic synthesis (T. W.Green and P. G. M. Wuts (1999) Protecting Groups in Organic Synthesis,3^(rd) edition, John Wiley and Sons, incorporated by reference withregard to protecting groups). These groups are removed at a convenientstage of the compound synthesis using methods that are readily apparentto those skilled in the art. The selection of processes as well as thereaction conditions and order of their execution shall be consistentwith the preparation of the compounds of Formula I and Formula Ia.

In all of the synthetic descriptions that follow, the variables ring A,ring B, D, E, J, R¹, R², R³, R⁴, m and n are as described for Formula Iand Formula Ia unless otherwise noted.

General Methods of Synthesizing Compounds of Formula I and Formula Ia

General Method 1: Bond formation between Formula II and Formula III withnucleophilic substitution/displacement of X by N.

Compounds of Formula I can be prepared by nucleophilic displacement of Xfrom a compound of Formula II with the N of a compound of Formula III.In Formula II, X is a suitable leaving group, for example, a halogenatom (e.g., chloride, bromide or iodide), a triflate, or a tosylategroup. The reaction takes place in a suitable organic solvent (e.g.,MeOH, EtOH, or acetonitrile) with or without a promoter (e.g. NaI) at atemperature of room temperature to 160° C. using conventional ormicrowave heating. When NHR³R⁴ is a salt (e.g., HCL ortrifluoroacetate), a base (e.g., Et₃N or (iPr)₂NEt) is added to thereaction mixture. Compounds of Formula III can be obtained commerciallyfrom conventional suppliers such as Aldrich, for example, or can besuitably prepared from commercially available starting materials by oneskilled in the art of organic chemistry. Compounds of Formula II can bereadily prepared through a Suzuki reaction involving compounds ofFormula IV with or without additional synthetic manipulation by meansknown to one skilled in the art of organic chemistry.General Method 2: Bond Formation between Formula IV and Formula V.

Compounds of Formula I can be prepared by reaction of a compound ofFormula IV where X is a leaving group (eg. halogen, or triflate) with acompound of Formula V where Z is a boronate, boronic acid, halogen, ortriflate, for example, and R³ could be a protecting group which is laterremoved in a separate step. The reaction occurs under Suzuki reactionconditions in a suitable organic solvent such as acetonitrile, in thepresence of a suitable catalyst such as (Ph₃P)₄Pd or PdCl₂(dppf), and inthe presence of an inorganic base such as Na₂CO₃ with or without theaddition of water at a temperature ranging from room temperature to 100°C.

General Method 3: Bond cleavage between N and R⁴ of Formula VI bydeprotection as of a basic amine as last step.

Compounds of Formula I can be readily prepared from compounds of FormulaVI, which may have been rendered using a similar procedure as describedin General Method 2, wherein R³ of Formula V is now a suitableprotecting group (ie. Boc). The protecting group is then removed usingknown literature procedures to produce a compound of Formula I whereinR³ is —H.

General Method 4: Bond formation between Formula VII and a ketone oraldehyde by reductive alkylation of NHR³.

Compounds of Formula I can be prepared from compounds of Formula VII byreductive alkylation with a ketone or aldehyde in a suitable solventsuch as MeOH or CH₂Cl₂, in the presence of a reducing agent such assodium cyanoborohydride, sodium (triacetoxy)borohydride or PS-BH₃CN,with or without acetic acid, at a temperature from room temperature to50° C. Sometimes it was found to be advantageous to react compounds ofFormula VII where R³ is H, with the ketone or aldehyde in a suitablesolvent such as benzene or toluene, at reflux temperature, underDean-Stark conditions before the addition of the reducing agent. In thisprocedure R⁵ and R⁶ may together form a ketone; or when R⁵ is hydrogen,R⁵ and R⁶ may form an aldehyde.

Compounds of Formula Ia can be prepared in a similar manner using thereductive alkylation conditions described. Compounds of Formula VIIIacan be prepared via Suzuki coupling between a compound of formula IVwhere X is a leaving group (eg. halogen, or triflate) and anappropriately substituted tetrahydroisoquinoline derivative where Z is aboronate, boronic acid, halogen, or triflate, for example, and R³ couldbe a protecting group which is later removed in a separate step. Thereaction occurs under Suzuki reaction conditions in a suitable organicsolvent such as acetonitrile, in the presence of a suitable catalystsuch as (Ph₃P)₄Pd or PdCl₂(dppf), and in the presence of an inorganicbase such as Na₂CO₃ with or without the addition of water at atemperature ranging from room temperature to 100° C.

General Method 5: Bond formation between Formula IX and Formula III byreductive alkylation

Compounds of Formula I, where D is CH₂ and J is a bond, can be preparedfrom compounds of Formula IX by reaction with compounds of Formula IIIin the presence of a reducing agent such as NaCN(BH)₃, NaBH(OAc)₃ orPS-BH₃CN, in an appropriate organic solvent such as MeOH ordichloromethane, with or without acetic acid, at a temperature rangingfrom room temperature to 50° C. Sometimes it was found advantageous toreact the compound of Formula IX with the compound of Formula III in asuitable solvent such as benzene or toluene, at reflux temperature,using Dean-Stark conditions prior to the addition of the reducing agent.

General Method 6: Functional group interconversion(s) to unmask E from Yin Formula X. Compounds of Formula I can be prepared by hydrolysis of anitrile to carboxamide (Y=CN, E=CONH₂) or aminolysis of an ester tocarboxamide (Y=CO₂R, E=CONH₂).

General Method 7: Removal of protecting group from Compounds of FormulaX wherein Y is a suitably protected heteroaryl or heterocyclyl.Compounds of Formula I can be readily prepared from compounds of FormulaX by removal of a protecting group (ie. POM, SEM, or Boc) using knownliterature procedures. Compounds of Formula X can be prepared using amethod described herein or through synthetic methods known to oneskilled in the art of organic chemistry.

EXPERIMENTAL

Reverse phase chromatography was performed on an Agilent 1100 seriesinstrument using a Phenomenex Luna 5 micron C18 column (150×21.1 mm).The gradient was 50% to 90% acetonitrile containing 0.1% trifluoroaceticacid/water containing 0.1% trifluoroacetic acid. Normal phasechromatography was performed on the ISCO Sg 100c combiflash system.

Intermediate A-1-1: 3′-hydroxy-4-biphenylcarboxamide

A mixture of 4-benzamide boronic acid (1.0 g, 0.006 mol), 3-bromophenol(1.0 g, 0.006 mol) and 30 mL of 0.4M Na₂CO₃ in 30 mL of acetonitrile wasdegassed for 10 min. with nitrogen.Tetrakis(triphenylphosphine)palladium (0.04 g, 0.03 mmol) was added andthe mixture was placed in a preheated oil bath at 90° C. After 2.5 hrthe hot reaction mixture was filtered through celite and concentrated toone-half volume in vacuo. The residue was extracted with mixtures ofethyl acetate and dichloromethane. The combined organic extracts weredried (Na₂SO₄), filtered and concentrated in vacuo to give3′-hydroxy-4-biphenylcarboxamide as a tan solid. (M+H) 214, t_(R) 1.8min. (LC/MS method A). This product was used without furtherpurification.

TABLE A Synthesis of Intermediates of Formula II CharacterizationExample # Structure and Name Data Comments D-1-1

4′-hydroxy-3- biphenylcarboxamide LC/MS (Method A) t_(R) 1.77 min (M +H) 214 Prepared in a manner similar to A-1-1 using 3-benzamide boronicacid and 4- bromophenol²⁾ H-1-1

3′-hydroxy- biphenylcarboxamide (M + H) 214, t_(R) 1.86 min (LC/MSMethod A) Prepared in a manner similar to A-1-1 using 3-benzamideboronic acid and 3- bromophenol J-1-1

4′-hydroxy-4- biphenylcarboxamide (M + H) 214, t_(R) 1.82 min (LC/MSMethod A) Prepared in a manner similar to A-1-1 using 4-benzamideboronic acid and 4- bromophenol L-1-2

3′-hydroxy-2-methyl-4- biphenylcarboxamide (M + H) 228, t_(R) 1.94 min(LC/MS Method A) Prepared in a manner similar to A-1-1 usingIntermediate IV-4 and 3-hydroxyphenyl boronic acid N-1-2

2-fluoro-3′-hydroxy-4- biphenylcarboxamide (M + H) 232, t_(R) 1.88 min(LC/MS Method A) Prepared in a manner similar to A-1-1 usingIntermediate IV-5 and 3-hydroxyphenyl boronic acid O-1-1

2′-fluoro-5′-hydroxy-4- biphenylcarboxamide (M + H) 232, t_(R) 1.88 min(LC/MS Method A) Prepared in a manner similar to A-1-1 using4-benzamideboronic acid and 3-bromo-4- fluorophenol HH-1-1

6-(3-hydroxyphenyl)-3- pyridinecarboxamide (M + H) 215, t_(R) 1.49 min(LC/MS method A) Prepared in a manner similar to A-1-1 using 6-chloro-3-pyridinecarboxamide and 3-hydroxyphenyl boronic acid JJ-1-1

5-(4-hydroxyphenyl)-3- pyridinecarboxamide ¹H NMR (400 MHz, DMSO-d₆) δppm 6.85 (d, 2H) 7.60 (m, 3H) 8.20 (s, 1H) 8.39 (s, 1H) 8.90 (d, 2H)9.72 (s, 1H) Prepared in a manner similar to A-1-1 using 5-bromo-3-pyridinecarboxamide and 4-hydroxyphenyl boronic acid¹⁾ KK-1-1

ethyl 5-(4-hydroxyphenyl)-2- thiophenecarboxylate ¹H NMR (400 MHz,CDCl₃) δ ppm 1.38 (t, 3H), 4.35 (q, 2H) 6.85 (d, 2H) 7.17 (s, 1H) 7.56(d, 2H) 7.74 (s, 1H) Prepared in a manner similar A-1-1 using ethyl5-chloro-2- thiophenecarboxylate and 4-hydroxy phenylboronic acid¹⁾KK-2-3

ethyl 5-(3-{[2,2-bis(ethyloxy) ethyl]oxy}phenyl)-2-thiophene carboxylate¹H NMR (400 MHz, CDCl₃) δ ppm 1.23 (t, 6H), 1.40 (t, 3H), 3.65 (m, 2H),3.78 (m, 2H), 4.08 (d, 2H), 4.36 (q, 2H) 4.85 (t, 1H) 6.90 (m, 1H)7.20-7.36 (m, 4H) 7.76 (s, 1H) Note 2 LL-1-3

2-(3-hydroxyphenyl)-1,3- thiazole-4-carboxamide ¹H NMR (400 MHz,DMSO-d₆) δ ppm 6.88 (m, 1H), 7.30 (m, 1H), 7.40 (m, 2H), 7.61 (s, 1H),7.80 (s, 1H), 8.22 (s, 1H), 9.78 (s, 1H) Prepared in a manner similarA-1-1 using Intermediate IV-18 and 3- hydroxyphenylboronic acid¹⁾ Note1: DME was used as the solvent in lieu of Acetonitrile. Note 2: Preparedin a manner similar to A-1-1 using a mixture of ethyl 5-chloro-2-thiophenecarboxylate and (3-{[2,2-Bis(ethyloxy)ethyl]oxy}phenyl)boronicacid²⁾ (prepared according to the procedure in Dack, Kevin Neil; Fray,Michael Jonathan; Whitlock, Gavin Alistair; Lewis, Mark Llewellyn;Thomson, Nicholas Murray: WO 2000/074681).

Compounds of Formula II

Example II-1 3′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide and3′-[(2-bromoethyl)oxy]-4-biphenylcarboxamide

Into three separate microwave vials was distributed equally a mixture of3′-hydroxy-4-biphenylcarboxamide (Intermediate A-1-1) (1.0 g, 0.005mol), 1-bromo-2-chloroethane (2.8 g, 0.02 mol) and potassium carbonate(2.8 g, 0.02 mol) in ethanol (2.2 mL) and water (1.8 mL) was placed in amicrowave at 150° C. until the reaction was complete as determined byLC/MS. The contents of the vials were combined and diluted with ethylacetate and water. The aqueous phase was extracted with ethyl acetate.The combined organic phase was dried (Na₂SO₄), filtered and concentratedin vacuo to give 3′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide and3′-[(2-bromoethyl)oxy]-4-biphenylcarboxamide as an off-white solid.LC/MS indicates that this product is a mixture of the chloroethoxy (M+H)276, 2.34 min. (LC/MS method A) and the bromoethoxy (M+H) 320, t_(R)2.42 min. in a ratio of ˜81/19% respectively. This product was usedwithout further purification.

Example II-2 3′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide

The title compound was prepared in a manner similar to that describedfor Example A-1-1 using a mixture of 4-benzamide boronic acid and3-bromophenyl 2-chloroethylether. (M+H) 276, t_(R) 2.32 min. (LC/MSmethod A).

Example II-3 4′-[(2-chloroethyl)oxy]-3-biphenylcarboxamide and4′-[(2-bromoethyl)oxy]-3-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 4′-hydroxy-3-biphenyl carboxamide (Intermediate D-1-1). Thechloroethoxy (M+H) 276, t_(R) 2.35 min. (LC/MS method A) and thebromoethoxy (M+H) 320, t_(R) 2.44 min. were obtained in a ratio of˜84/16% respectively.

Example II-4 4′-[(2-chloroethyl)oxy]-3-biphenylcarboxamide

The title compound was prepared in a manner similar to Example A-1-1using a mixture of 3-benzamide boronic acid and 4-bromophenyl2-chloroethylether with PdCl₂(dppf).CH₂Cl₂ in lieu of Pd(PPh₃)₄ in DME.Purification of the desired product was accomplished by eitherrecrystallization from EtOH or silica gel chromatography usingHexanes/Ethyl Acetate. (LC/MS Method A) t_(R) 2.33 min, m/z 276 (M+H).

Example II-5 3′-[(2-chloroethyl)oxy]-3-biphenylcarboxamide and3′-[(2-bromoethyl)oxy]-3-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 3′-hydroxy-3-biphenylcarboxamide (Intermediate H-1-1). Thechloroethoxy (M+H) 276, t_(R) 2.38 min. (LC/MS method A) and thebromoethoxy (M+H) 320, t_(R) 2.45 min. (LC/MS method A) were obtained ina ratio of ˜65/35% respectively.

Example II-6 4′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide and4′-[(2-bromo ethyl)oxy]-4-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 4′-hydroxy-4-biphenylcarboxamide (Intermediate J-1-1). LC/MS ofthe brown solid indicates that this product is a mixture of thechloroethoxy (M+H) 276, t_(R) 2.47 min. (LC/MS method A) and thebromoethoxy (M+H) 320, t_(R) 2.54 min. (LC/MS method A) in a ratio of˜74/26% respectively.

Example II-7 3′-[(2-chloroethyl)oxy]-2-methyl-4-biphenylcarboxamide and3′-[(2-bromo ethyl)oxy]-2-methyl-4-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 3′-hydroxy-2-methyl-4-biphenyl carboxamide (Intermediate L-1-2).LC/MS indicates that this product is a mixture of the chloroethoxy (M+H)290.2, t_(R) 2.42 min. (LC/MS method A) and the bromoethoxy (M+H) 334,t_(R) 2.50 min. (LC/MS method A) in a ratio of ˜73/27% respectively.

Example II-8 3′-[(2-chloroethyl)oxy]-2-methyl-4-biphenylcarboxamide

A mixture of 3′-hydroxy-2-methyl-4-biphenylcarboxamide (1.65 g, 0.007mol. Intermediate L-1-2), 2-chloroethyl-p-toluenesulfate (1.88 g, 0.008mol) and potassium carbonate (1.11 g, 0.008 mol) in acetonitrile (25 mL)was heated at reflux for 40 hr. The reaction mixture was concentrated invacuo to remove acetonitrile. The residue was partitioned between ethylacetate and water. The ethyl acetate phase was washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo. The residue was purifiedby silica gel chromatography to give3′-[(2-chloroethyl)oxy]-2-methyl-4-biphenylcarboxamide as a white solid.(M+H) 290, t_(R) 2.49 min. (LC/MS method B).

Example II-9 3′-[(2-chloroethyl)oxy]-2-fluoro-4-biphenylcarboxamide and3′-[(2-bromo ethyl)oxy]-2-fluoro-4-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 2-fluoro-3′-hydroxy-4-biphenyl carboxamide (Intermediate N-1-2).LC/MS indicates that this product is a mixture of the chloroethoxy (M+H)294, t_(R) 2.41 min. (LC/MS method A) and the bromoethoxy (M+H) 338,2.49 min. (LC/MS method A) in a ratio of ˜65/35% respectively.

Example II-10 5′-[(2-chloroethyl)oxy]-2′-fluoro-4-biphenylcarboxamideand 5′-[(2-bromo ethyl)oxy]-2′-fluoro-4-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 2′-fluoro-5′-hydroxy-4-biphenyl carboxamide (Intermediate O-1-1).LC/MS indicates that this product is a mixture of the chloroethoxy (M+H)294, t_(R) 2.38 min. (LC/MS method A) and the bromoethoxy (M+H) 338,t_(R) 2.45 min. (LC/MS method A) in a ratio of ˜74/26% respectively.

Example II-11 3′-[(3-chloropropyl)oxy]-4-biphenylcarboxamide and3′-[(3-bromo propyl)oxy]-4-biphenylcarboxamide

The mixture of title compounds was prepared similar to Example II-1using 3′-hydroxy-4-biphenylcarboxamide (Intermediate A-1-1) and1-bromo-3-chloropropane. LC/MS indicates that this product is a mixtureof the chloropropoxy (M+H) 290, t_(R) 2.57 min. (LC/MS method A) and thebromopropoxy (M+H) 334, t_(R) 2.62 min. (LC/MS method A) in a ratio of˜75/25% respectively.

Example II-12 6-{3-[(2-chloroethyl)oxy]phenyl}-3-pyridinecarboxamide

The title compound was prepared in a manner similar to Example II-8using 6-(3-hydroxyphenyl)-3-pyridinecarboxamide (Intermediate HH-1-1).¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.95 (t, 2H) 4.38 (t, 2H) 7.05 (d, 1H)7.40 (t, 1H) 7.60 (br, 1H) 7.75 (m, 2H) 8.10 (d, 1H) 8.20 (br, 1H) 8.28(d, 1H) 9.05 (s, 1H).

Example II-13 5-{4-[(2-chloroethyl)oxy]phenyl}-3-pyridinecarboxamide

The title compound was prepared in a similar fashion to Example II-8using 5-(4-hydroxyphenyl)-3-pyridinecarboxamide (Intermediate JJ-1-1).¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.95 (t, 2H) 4.35 (t, 2H) 7.10 (d, 2H)7.60 (s, 1H) 7.75 (d, 2H) 8.12 (s, 1H) 8.40 (s, 1H) 8.92 (s, 1H) 8.98(s, 1H).

Example II-14 5-{4-[(2-chloroethyl)oxy]phenyl}-2-thiophenecarboxamide

To a suspension of ammonium chloride (2.12 g, 39.6 mmol) in 10 ml oftoluene at 5° C. was added dropwise 19.8 ml of 2M trimethylaluminum intoluene solution. The mixture was stirred for 2 h at the roomtemperature and ethyl 5-(4-hydroxyphenyl)-2-thiophene carboxylate(Intermediate KK-1-1) (1.98 g, 7.03 mmol) was added. The resultingmixture was heated at 55-60° C. for 15 h, cooled to 5° C. and quenchedwith ethanol (10 ml). All solvents were removed in vacuo and the residuewas treated with 80 ml of 0.5M HCl solution. A yellow solid wascollected by filtration, washed with water and air-dried (1.64 g). Theproduct was added to a mixture of 2-chloroethyl p-toluenesulfonate (4.07ml, 22.5 mmol) and potassium carbonate (3.11 g, 22.5 mmol) in 100 ml ofacetonitrile. After heating at reflux for 40 h, the reaction mixture wasfiltered to remove the solids, concentrated to dryness in vacuo andpurified by silica gel column chromatography using Hexanes and EtOAc togive the title compound as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.90 (t, 2H), 4.28 (t, 2H) 7.00 (d, 2H)7.39 (m, 2H) 7.60 (m, 3H) 7.90 (s, 1H); (M+H) 282, t_(R) 2.28 min (LC/MSmethod A).

Example II-15 5-{3-[(2-chloroethyl)oxy]phenyl}-2-thiophenecarboxamide

Step 1: Ethyl 5-{3-[(2-oxoethyl)oxy]phenyl}-2-thiophenecarboxylate

Ethyl 5-(3-{[2,2-bis(ethyloxy)ethyl]oxy}phenyl)-2-thiophenecarboxylate(Intermediate KK-2-3) (1.41 g, 3.87 mmol) was dissolved in 20 ml ofchloroform and cooled to 0° C. 5 ml of 50% aqueous trifluoroacetic acidsolution was added. The mixture was stirred for 15 h at room temperatureand 6 h at 65° C., cooled, diluted with chloroform and neutralized withsaturated sodium bicarbonate solution. The organic layer was separated,washed with brine, dried over magnesium sulfate and concentrated invacuo. The residue was purified by silica gel column chromatography (10to 50% ethyl acetate in hexanes) to afford the title compound as a whitecrystalline solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.40 (t, 3H), 4.38 (q, 2H) 4.63 (s, 2H)6.85 (m, 1H) 7.24-7.38 (m, 4H) 7.77 (s, 1H), 9.90 (s, 1H).

Step 2: 5-(3-Hydroxyphenyl)-2-thiophenecarboxamide

The mixture of ethyl5-{3-[(2-oxoethyl)oxy]phenyl}-2-thiophenecarboxylate (1.3 g, 4.48 mmol),2N aqueous lithium hydroxide solution (5 ml, 10 mmol) andtetrahydrofuran (10 ml) was heated to reflux for 12 h. The reactionmixture was cooled, concentrated in vacuo to remove tetrahydrofuran,acidified to pH1-2 with 2N HCl, and extracted with ethyl acetate threetimes. The combined extracts were washed with brine, dried overmagnesium sulfate and concentrated in vacuo. The solid residue (0.75 g)was dissolved in dry tetrahydrofuran (15 ml) and cooled to 0° C.(Chloromethylene)dimethylammonium chloride (Aldrich, 0.52 g, 4 mmol) wasadded in one portion. The mixture was stirred at 0° C. for 4 h. Thepre-cooled (0° C.) mixture of 28% ammonium hydroxide aqueous solution(2.5 ml) and water (2.5 ml) was added, and the reaction mixture wasstirred at the room temperature. Tetrahydrofuran was removed in vacuoand the residue was extracted with ethyl acetate three times. Thecombined extracts were washed with brine, dried over magnesium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (80% ethyl acetate in hexanes) to give the title compoundas a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.75 (d, 1H) 7.01 (s, 1H) 7.08 (d, 1H)7.20 (t, 1H) 7.40 (m, 2H) 7.65 (d, 1H) 7.97 (br., 1H) 9.62 (s, 1H);(M+H) 220, t_(R) 1.78 min (LC/MS method A).

Step 3: 5-{3-[(2-Chloroethyl)oxy]phenyl}-2-thiophenecarboxamide

5-(3-Hydroxyphenyl)-2-thiophenecarboxamide (0.31 g, 1.41 mmol),2-chloroethyl p-toluenesulfonate (1.327 g, 5.65 mmol) and potassiumcarbonate (0.782 g, 5.65 mmol) in 20 ml of acetonitrile were heated toreflux for 15 h. The reaction mixture was concentrated in vacuo andpurified by silica gel column chromatography (50 to 80% ethyl acetate inhexanes) to give the title compound as a white solid.

¹H NMR (400 MHz, Acetone-d₆) δ ppm 3.95 (t, 2H) 4.40 (t, 2H) 6.68 (br.,1H) 7.00 (d, 1H) 7.28-7.40 (m, 3H) 7.50 (d, 1H) 7.72 (d, 1H).

Example II-162-{3-[(2-chloroethyl)oxy]phenyl}-1,3-thiazole-4-carboxamide

The title compound was prepared in a similar fashion to Example II-8using 2-(3-Hydroxyphenyl)-1,3-thiazole-4-carboxamide (IntermediateLL-1-3). (M+H) 283, t_(R) 2.34 min (LC/MS method A).

Example II-172-{4-[(2-chloroethyl)oxy]phenyl}-1,3-thiazole-4-carboxamide

Step 1: 2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxylic Acid

4-Hydroxybenzenecarbothioamide (1.53 g, 10 mmol) and potassium hydroxide(1.50 g, 26.8 mmol) were dissolved in a mixture of 60 ml of water and 15ml of methanol. A solution of bromopyruvic acid (1.67 g, 10 mmol) in 10ml of methanol was added dropwise at room temperature. The resultingmixture was heated to reflux for 1.5 h, cooled to room temperature,poured into 100 ml of water and adjusted with 0.2N HCl solution to pH2.The mixture was placed in a refrigerator for 15 h. The title compoundwas obtained by filtration as a brown solid. ¹H NMR (400 MHz, DMSO-d₆) δppm 6.82 (d, 2H), 7.78 (d, 2H), 8.37 (s, 1H), 10.05 (s, 1H), 13.00 (s,1H).

Step 2: 2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxamide

2-(4-Hydroxyphenyl)-1,3-thiazole-4-carboxylic acid (0.835 g, 3.77 mmol)was dissolved in 20 ml of dry tetrahydrofuran and cooled to 0° C.(Chloromethylene)dimethylammonium chloride (0.58 g, 4.53 mmol) was addedin one portion. The mixture was stirred at 0° C. for 5 h. 28% Ammoniumhydroxide aqueous solution (5 ml) was added, and the reaction mixturewas stirred for 15 h at the room temperature. The organic solvent wasremoved in vacuo and the residue was partitioned between ethyl acetateand saturated sodium carbonate solution. The organic layer was separatedand the aqueous phase was extracted twice with ethyl acetate. Thecombined extracts were washed with brine, dried over magnesium sulfateand concentrated in vacuo. The residue was purified by silica gel columnchromatography (0 to 10% methanol in dichloromethane) to give the titlecompound as beige solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 6.83 (d, 2H) 7.60 (s, 1H) 7.80 (m, 3H)8.12 (s, 1H) 10.05 (s, 1H); (M+H) 221, t_(R) 1.69 min (LC/MS method A).

Step 3: 2-{4-[(2-Chloroethyl)oxy]phenyl}-1,3-thiazole-4-carboxamide

Proceeding in a similar manner to Example II-8 using2-(4-hydroxyphenyl)-1,3-thiazole-4-carboxamide gave the title compoundas a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 3.82 (t, 2H) 4.30 (t, 2H) 5.68 (s, 1H)7.00 (d, 2H) 7.28 (s, 1H) 7.90 (d, 2H) 8.09 (s, 1H)

Compounds of Formula III

Example III-1 4,4-dimethylcyclohexylamine hydrochloride

Prepared similarly to the procedure of Johnston, T. P.; McCaleb, G. S.;Opliger, P. S.; Laster, W. R.; Montgomery J. A. J. Med. Chem. 1971, 14(7), 600.

Step 1: 4,4-Dimethylcyclohexanone

A mixture of 4,4-dimethyl-2-cyclohexene-1-one (5.5 g) and 10% Pd/C (0.25g, wet, Degussa type E101) in EtOAc (50 mL) was hydrogenated under 15psi for 3 h at room temperature. The mixture was filtered through Celiteand the filtrate was concentrated in vacuo affording the title compoundas a colorless solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (s, 6H), 1.65(t, J=7 Hz, 4H), 2.35 (t, J=7 Hz, 4H).

Step 2: 4,4-dimethylcyclohexanone oxime

To a solution of 4,4-dimethylcyclohexanone (3.0 g, 0.024 mole) andhydroxylamine hydrochloride (2.2 g, 0.031 mole) in ethanol (15 mL) andwater (20 mL) at room temperature was added a solution of sodiumcarbonate (3.3 g, 0.031 mol) in water (10 mL), dropwise. The mixture washeated under reflux for 3 hr, cooled to room temperature and ethanol wasremoved in vacuo. The aqueous residue was extracted several times withethyl acetate, combined extracts were dried over MgSO₄ and concentratedin vacuo affording the title compound as a white solid, used withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93 (s, 6H), 1.28(t, J=6.6 Hz, 2H), 1.35 (t, J=6.6 Hz, 2H), 2.11 (t, J=6.6 Hz, 2H), 2.36(t, J=6.6 Hz, 2H), 10.12 (s, 1H).

Step 3: 4,4-dimethylcyclohexylamine hydrochloride

A mixture of 4,4-dimethylcyclohexanone oxime (3.0 g, 0.021 mole) andRaney 2800 Nickel (0.8 g, slurry in water) in ethanol (100 mL) washydrogenated under 50 psig H₂ using a Parr hydrogenation apparatus.After hydrogen absorption ceased the mixture was filtered throughCelite. To the filtrate was added a solution of HCl in Et₂O (50 mL of a1M solution), the mixture was concentrated in vacuo. The residue wastriturated with diethyl ether, solid was collected by filtration, washedwith diethyl ether and air dried to give the title compound as a whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 0.86 (s, 3H), 0.87 (s, 3H), 1.19(m, 2H), 1.36 (m, 2H), 1.48 (m, 2H), 1.70 (m, 2H), 2.87 (m, 1H), 7.93(br. s, 3H).

Example III-2 [(4,4-dimethylcyclohexyl)methyl]amine hydrochloride

Step 1: (4,4-dimethylcyclohexylidene)methyl methyl ether

To a mixture of methoxymethyl triphenylphosphonium chloride (35.5 g,0.104 mol) in THF (400 mL) at 0° C. was added n-BuLi (33.1 mL of a 2.8Msolution in hexanes; 0.095 mol). The mixture was stirred at 0° C. for 30min., cooled to −78° C. and a solution of 4,4-dimethyl cyclohexanone(10.0 g, 0.079 mol) in THF (100 mL) was added, dropwise. After 1 hr at−78° C. the mixture was slowly warmed to 0° C., diluted with satdammonium chloride (400 mL) and ethyl acetate (100 mL) and stirred atroom temperature for 48 hr. Layers were separated and the aqueous phasewas extracted with ethyl acetate. Combined organics were washed withbrine, dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was triturated with hexanes, solids were removed by filtrationand the filtrated was concentrated in vacuo. The residue was dissolvedin dichloromethane (40 mL), PS-TsNHNH₂ (8 g; ca. 3.7 mmol/g) and aceticacid (2 drops) were added and the mixture was stirred at roomtemperature for 24 hr. Resin was removed by filtration and washed(CH₂Cl₂, MeOH, CH₂Cl₂). Combined filtrate/washings were concentrated invacuo, affording (4,4-dimethyl cyclohexylidene)methyl methyl ether as anoil. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.91 (s, 6H); 1.27 (m, 5H); 1.95 (m,2H); 2.18 (m, 2H); 3.52 (s, 3H).

Step 2: 4,4-dimethylcyclohexanecarbaldehyde

A solution of (4,4-dimethyl cyclohexylidene)methyl methyl ether (6.7 g,0.043 mol) in THF (200 mL) containing 6M HCl (aq) (60 mL) was stirred atroom temperature for 24 hr. The reaction mixture was diluted with amixture of ethyl ether, hexanes, brine and water. The mixture wasseparated and the aqueous phase was extracted with ethyl ether. Thecombined organic phase was washed with brine, dried over Na₂SO₄, andconcentrated in vacuo, affording 4,4-dimethylcyclohexanecarbaldehyde asa yellow oil, used without further purification.

Step 3: [(4,4-dimethylcyclohexyl)methyl](phenylmethyl)amine

A solution of 4,4-dimethylcyclohexanecarbaldehyde (6.6 g, 0.047 mol),benzylamine (5.0 g, 0.047 mol) and acetic acid (1 mL) in methanol (60mL) was stirred for 30 min at room temperature. Sodiumtriacetoxyborohydride (10.0 g, 0.047 mol) was added in one portion andthe mixture was stirred at room temperature for 16 hr. The reactionmixture was concentrated in vacuo and partitioned betweendichloromethane and water. The organic phase was washed with brine,silica gel was added and the mixture was concentrated in vacuo. Theresidue was purified by flash chromatography (CH₂Cl₂/MeOH), affording[(4,4-dimethyl cyclohexyl)methyl](phenylmethyl)amine as a white solid.(M+H) 232, 1.76 min. (LC/MS method B).

Step 4: [(4,4-dimethylcyclohexyl)methyl]amine hydrochloride

A mixture of [(4,4-dimethylcyclohexyl)methyl](phenylmethyl)amine (4.37g, 0.019 mol) and 10% Pd/C (50% w/w with water) (0.75 g) in ethanol (100mL) was hydrogenated under 50 psi H₂ using a Parr hydrogenationapparatus for 24 h and filtered through Celite. To the filtrate wasadded HCl in Et₂O (30 mL of a 1M solution) and the mixture wasconcentrated in vacuo. The residue was triturated with Et₂O, filtered,washed (Et₂O) and dried to give [(4,4-dimethylcyclohexyl)methyl]aminehydrochloride as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.83 (s,3H); 0.86 (s, 3H); 1.11 (m, 4H); 1.33 (m, 2H); 1.46 (m, 1H); 1.53 (m,2H); 2.64 (br s, 2H); 7.91 (br s, 3H).

Example III-3 rac 3,3-dimethylcyclohexylamine hydrochloride

The title compound was prepared from 3,3-dimethylcyclohexanone in amanner similar to Example III-1 steps 2-3, with the exception that theintermediate oxime was not characterized. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.85 (s, 3H); 0.90 (s, 3H); 0.97-1.16 (m, 3H); 1.29 (br d, 1H);1.34-1.46 (m, 1H); 1.53-1.63 (m, 2H); 1.90 (br d, 1H); 3.05 (m, 1H);7.99 (br s, 3H).

Example III-4 [(1S)-3,3-dimethylcyclohexyl]amine hydrochloride and[(1R)-3,3-dimethylcyclohexyl]amine hydrochloride

Step 1: rac-phenyl methyl (3,3-dimethylcyclohexyl)carbamate

To a solution of (3,3-dimethylcyclohexyl)amine hydrochloride (10.0 g,0.060 mol) and N,N-diisopropylethylamine (15.8 g, 0.12 mol) inacetonitrile (125 mL) at ice bath temperature was added a solution ofbenzyl chloroformate (11.4 g, 0.067 mol) in acetonitrile (25 mL),dropwise. The mixture was stirred overnight, gradually warming toambient temperature, and concentrated in vacuo. The residue waspartitioned between ethyl acetate/5% citric acid solution and the layerswere separated. The organic layer was washed with brine, dried overNa₂SO₄, adsorbed onto silica gel and purified by flash chromatography(CH₂Cl₂/hexanes) affording the title compound as a colorless oil. ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 0.85 (s, 6H), 0.92-1.02 (m, 3H), 1.25 (d, 1H),1.36-1.52 (m, 3H), 1.76 (br. d, 1H), 3.36-3.44 (m, 1H), 4.96 (s, 2H),7.10 (d, 1H), 7.27-7.36 (m, 5H).

Step 2: phenylmethyl[(1S)-3,3-dimethylcyclohexyl]carbamate andphenylmethyl [(1R)-3,3-dimethylcyclohexyl]carbamate

rac-Phenylmethyl (3,3-dimethylcyclohexyl)carbamate (11.2 g) wasseparated into enantiomers on a 30 mm Chiralpak AS column bysupercritical fluid chromatography (CO₂/EtOH, 75:4 g/min respectively at140 bar, 40° C.). Earlier-eluting enantiomer: ¹H NMR (400 MHz, DMSO-d₆)δ ppm: 0.85 (s, 6H), 0.93-1.01 (m, 3H), 1.25 (d, 1H), 1.33-1.52 (m, 3H),1.75 (br d, 1H), 3.35-3.44 (m, 1H), 4.96 (s, 2H), 7.08 (d, 1H),7.25-7.35 (m, 5H). Later-eluting enantiomer: ¹H NMR (400 MHz, DMSO-d₆) δppm: 0.85 (s, 6H), 0.92-1.01 (m, 3H), 1.25 (d, 1H), 1.33-1.52 (m, 3H),1.75 (br dl 1H), 3.36-3.44 (m, 1H), 4.96 (s, 2H), 7.08 (d, 1H),7.26-7.35 (m, 5H). Comparison of experimentally measured vibrationalcircular dichroism (VCD) spectra with the calculated (ab initio) VCDspectrum for [(1R)-3,3-dimethylcyclohexyl]carbamate indicated thelater-eluting enantiomer had the (R)-configuration.

Step 3: [(1S)-3,3-dimethylcyclohexyl]amine hydrochloride and[(1R)-3,3-dimethylcyclohexyl]amine hydrochloride

The preparation of [(1S)-3,3-dimethylcyclohexyl]amine hydrochloride isgiven as representative.Phenylmethyl[(1S)-3,3-dimethylcyclohexyl]carbamate (1.0 g, 4.0 mmol) and10% Pd/C (0.15 g) in 10 mL of MeOH was stirred under an atmosphere of H₂for 24 hours and filtered through Celite. To the filtrate was added HClin Et₂O (2.5 mL of a 1M solution), the mixture was aged overnight atroom temperature and concentrated in vacuo. The residue was trituratedwith Et₂O, solid was collected by filtration washed (Et₂O) and dried invacuo affording the title compound as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 0.89 (s, 3H), 0.93 (s, 3H), 1.00-1.17 (m, 3H), 1.33 (br.d, 1H), 1.38-1.49 (br. q, 1H), 1.58-1.63 (m, 2H), 1.92 (br d, 1H),3.06-3.14 (m, 1H), 7.86 (s, 3H). [(1R)-3,3-dimethylcyclohexyl]aminehydrochloride was obtained from [(1R) 3,3-dimethylcyclohexyl]carbamateaccording to the procedure described above for[(1S)-3,3-dimethylcyclohexyl]amine hydrochloride. ¹H NMR (400 MHz,DMSO-d₆) δ ppm: 0.85 (s, 3H), 0.90 (s, 3H), 0.96-1.14 (m, 3H), 1.29 (br.d, 1H), 1.35-1.45 (br q., 1H), 1.53-1.61 (m, 2H), 1.89 (br d, 1H),3.02-3.09 (m, 1H), 7.88 (s, 3H).

Example III-5 3,3,5,5-tetramethycyclohexylamine hydrochloride

The title compound was prepared from 3,3,5,5-tetramethylcyclohexanone ina manner similar to Example III-1 steps 2-3, with the exception that theintermediate oxime was not characterized. ¹H NMR (400 MHz, DMSO-d₆) δppm 0.89 (s, 6H); 0.96 (s, 6H); 0.92-1.12 (m, 3H); 1.22 (br d, 1H); 1.67(br s, 2H); 3.24 (m, 1H); 8.01 (br s, 3H).

Example III-6 isohexylamine hydrobromide

Step 1: 2-(4-methylpentyl)-1H-isoindole-1,3(2H)-dione

To a solution of 1-bromo-4-methylpentane (5.0 g, 0.030 mol) in DMF (20mL) was added potassium phthalimide (5.9 g, 0.032 mol) in one portion atroom temperature. After stirring at room temperature of 1 hr, themixture was heated at 55° C. for 16 hr. Chloroform (30 mL) was added tothe reaction mixture and the resulting mixture was poured into water(100 mL). The aqueous phase was extracted with chloroform and thecombined organic phase was washed with 0.25 M NaOH (aq) and water. Theorganic phase was dried (Na₂SO₄), filtered and concentrated in vacuo togive 2-(4-methylpentyl)-1H-isoindole-1,3(2H)-dione as a pale yellow oil.(M+H) 232, 2.80 min. (LC/MS method A).

Step 2: isohexylamine hydrobromide

A solution of 2-(4-methylpentyl)-1H-isoindole-1,3(2H)-dione (6.5 g,0.028 mol) in 48% aqueous hydrogen bromide (10 mL) and acetic acid (25mL) was heated under reflux for 28 hr. The hot reaction mixture wasdiluted water (40 mL), chilled in an ice bath and aged at roomtemperature for 18 hr. Precipitated solids were separated by filtration,and the filtrate was concentrated the in vacuo. Residue from thefiltrate was triturated with water, insoluble solids were separated byfiltration and the filtrate was concentrated in vacuo. Residue from thefiltrate was triturated with ether, solids were collected by filtration,washed with ether and dried to give the title compound as a beige solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.84 (d, 3H); 0.96 (s, 3H); 1.16 (m,2H); 1.50 (m, 3H); 2.73 (m, 2H); 7.68 (br s, 3H).

Example III-7 2-cyclohexylethylamine hydrochloride

A mixture of 2-(1-cyclohexenyl)ethylamine (5.60 g) and 10% Pd/C (0.6 g,wet, Degussa type E101) in 60 mL of methanol was hydrogenated under 55psi H₂ using a Parr hydrogenation apparatus for 5 h at room temperature.The mixture was filtered through Celite and the filtrate wasconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ (5 mL) andHCl in Et₂O (3 mL of a 1M solution) was added. Solid was collected byfiltration, affording the title compound as a white solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 0.85 (m, 2H), 1.02-1.36 (m, 5H), 1.41 (m, 2H),1.55-1.76 (m, 4H), 2.75 (m, 2H), 7.90 (br, 3H).

Example III-8 (2-cyclohexyl-2,2-difluoroethyl)amine hydrochloride

Step 1: ethyl cyclohexyl(oxo)acetate

To a suspension of magnesium turnings (2.20 g, 90.32 mmol) in THF (100mL) was added cyclohexyl bromide (9.27 mL, 75.27 mmol). The mixture wassonicated (note 1) for 30 min, the supernatant liquid was decanted intoan addition funnel and added to a solution of diethyloxalate (22.0 g,146.14 mmol) in THF (240 mL) at −10° C. over one hour. After 30 minutes,10% HCl (75 mL) was added the mixture was and stirred 15 minutes. Layerswere separated and the aqueous layer was extracted with Et₂O (100 mL).Combined organics were washed (brine), dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatography(EtOAc/hexanes), affording the title compound as a clear oil. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.15-1.40 (m, 5H) 1.56-1.94 (m, 8H) 2.97-3.05 (m,1H) 4.30 (q, J=7.32 Hz, 2H).

Note 1: A conventional ultrasonic cleaning bath was used.

Step 2: ethyl cyclohexyl(difluoro)acetate

To a solution of ethyl cyclohexyl(oxo)acetate (2.94 g, 15.95 mmol) in 5mL CH₂Cl₂ at −5° C. was added bis(2-methoxyethyl)aminosulfur trifluoride(deoxo-fluor; 5.0 mL, 27 mmol) in 5 mL CH₂Cl₂. EtOH (0.185 mL, 0.78mmol) was added, the mixture was stirred 16 hours at ambient temperatureand poured onto ice. The layers were separated and the aqueous layer wasextracted with CH₂Cl₂ (10 mL). Combined organics were washed (satdNaHCO₃, brine), dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography (EtOAc/hexanes), affording thetitle compound as a clear oil. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.13-1.37(m, 5H) 1.48-1.85 (m, 8H) 1.98-2.08 (m, 1H) 4.30 (q, J=7.08 Hz, 2H).

Step 3: 2-cyclohexyl-2,2-difluoroacetamide

A solution of ethyl cyclohexyl(difluoro)acetate (2.63 g, 12.75 mmol) inEtOH (6 mL) was sparged with anhyd ammonia for 15 minutes at ambienttemperature. The mixture was sealed in a pressure tube and allowed tostand overnight. Volatiles were removed in vacuo and the solid residuewas recrystallized from dichloromethane-hexanes affording the titlecompound as a waxy solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.13-1.37 (m,5H) 1.48-1.85 (m, 8H) 1.98-2.08 (m, 1H) 4.30 (q, J=7.08 Hz, 2H)

Step 4: (2-cyclohexyl-2,2-difluoroethyl)amine hydrochloride

To a solution of the 2-cyclohexyl-2,2-difluoroacetamide in 20 mL of THFat ambient temperature, under nitrogen, was added borane-tetrahydrofurancomplex (56 mL, 56 mmol). The mixture was heated under reflux for 18hours, cooled to ambient temperature, and MeOH was added slowly, withstirring. The mixture was heated under reflux for 30 minutes, cooled andconcentrated in vacuo. Aq. HCl (5 mL, 6M) was added, the mixture washeated briefly (ca. 1 min) under reflux and cooled. The mixture pH wasadjusted to ca. 10 with satd NaHCO₃ and the whole was extracted withCH₂Cl₂ (×2). Combined extracts were dried over Na₂SO₄ and concentratedin vacuo. The residue was taken up in EtOH and briefly sparged with astream of anhyd HCl (ca. 1 min). Precipitated solid was collected byfiltration and air-dried affording the title compound as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.25 (m, 5H) 1.56-1.65 (m, 1H)1.67-1.81 (m, 4H) 1.87-1.98 (m, 1H) 3.35 (t, J=16.4 Hz, 2H) 8.37 (br. s,2H).

Example III-9 5,6-difluoro-2,3-dihydro-1H-inden-2-amine (andCorresponding Hydrochloride Salt)

Step 1: 5,6-difluoro-2,3-dihydro-1H-inden-1-one

To a solution of 3,4-difluorophenyl propionic acid (30.45 g; 163.6 mmol)and 2 drops of DMF in CH₂Cl₂ (200 mL) was added oxalyl chloride (41.4 g,327 mmol) over 20 min. The resulting solution was stirred for 24 hr andconcentrated in vacuo (chased 1×PhMe, ca. 100 mL). The residue wasdissolved in CS₂ (300 mL), cooled to 0° C. and AlCl₃ (76.4 g, 573 mmol)was added over 10 min. The mixture was stirred 30 min at 0° C., thenheated under reflux for 4 hr. Upon cooling to room temperature thesolution was carefully poured onto crushed ice, the carbon disulfidelayer was separated and the aqueous layer extracted with EtOAc. Combinedorganics were dried over MgSO₄ and the concentrated in vacuo. Theresidue was purified by flash chromatography (EtOAc/hexanes), affordingthe title compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.50 (t,1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69(m, 2H).

Step 2: 5,6-difluoro-2,3-dihydro-1H-inden-2-amine

To a solution of 5,6-difluoro-2,3-dihydro-1H-inden-1-one (4.60 g, 27.4mmol) in MeOH (90 mL) at 40° C. was added isoamyl nitrite (4.17 g, 35.6mmol) followed by concentrated HCl (2.7 mL). Upon heating for 45 min thesolution was cooled to room temperature and water was added.Precipitated solid was collected by filtration and rinsed thoroughlywith water affording 3.97 g of a light orange solid. The solid wasdissolved in HOAc (100 mL), conc HCl (8 mL) was added, followed by 10%Pd/C (1.07 g). The mixture was hydrogenated under 50 psi H₂ for 24 hrusing a Parr hydrogenation apparatus, and filtered through a bed ofCelite (CHCl₃ wash). The filtrate was concentrated in vacuo and theresidue was dissolved in water. The aqueous solution was basified withsolid K₂CO₃, extracted with CHCl₃ (3×), combined extracts were driedover MgSO₄ and concentrated in vacuo. The residue was purified by flashchromatography (MeOH/CH₂Cl₂) affording the title compound as a brownoil. ¹H NMR (400 MHz, CDCl₃) δ 6.95 (t, 2H, J=8.9 Hz), 3.83 (m, 1H),3.10 (dd, 2H, J=15.8 & 6.8 Hz), 2.60 (dd, 2H, J=15.8 & 5.0 Hz); (M+H)170, 0.68 min (LC/MS method A).

The above oil was dissovled in Et₂O (ca. 5 mL) and HCl in dioxane (4 mLof a 4M solution) was added. Precipitated solid was triturated with Et₂Oand collected by filtration, affording the corresponding hydrochloridesalt.

Example III-10 rac 5-fluoro-2,3-dihydro-1H-inden-2-amine (andCorresponding Hydrochloride Salt)

To a solution of 5-fluoro-1-indanone (10.0 g; 66.7 mmol) in MeOH at 40°C. was added n-butyl nitrite (13.2 mL; 113 mmol), dropwise over 3minutes, followed by conc HCl (10 mL), dropwise at such a rate that theinternal temp was maintained below 55° C. The mixture was stirred 30 minand concentrated in vacuo. The residue was diluted with EtOAc and sat'dNaHCO₃, filtered, and the layers were separated. The aqueous layer wasextracted with EtOAc, combined organics were washed (H₂O, brine), driedover Na₂SO₄, and concentrated in vacuo. The residue was purified byflash chromatography (EtOAc/hexanes), affording an 7.59 g of an orangesolid. The solid was dissolved in HOAc/H₂SO₄ (250/12.5 mL respectively),10% Pd—C was added (4.5 g; wet, DeGussa type E101) and the mixture washydrogenated under 50 psi H₂ for 18 h using a Parr hydrogenationapparatus. The mixture was filtered through Celite (H₂O wash), partiallyconcentrated to an aqueous mixture, and the mixture pH was adjusted toca. 11 by addition of 1N NaOH. The whole was extracted with CHCl₃ (×5),combined organics were washed (brine), dried over Na₂SO₄, andconcentrated in vacuo, affording the title compound as an amber oil. ¹HNMR (400 MHz, DMSO-d₆) δ 1.69 (br. s, 2H), 2.53 (m, 2H, overlappingsolvent), 2.99 (m, 2H), 3.69 (quint, J=6.2 Hz, 1H), 6.89 (partiallyresolved ddd, J=9.8, ˜7.7, 2.5 Hz, 1H), 6.99 (partially resolved dd,J=9.3, ˜2.3 Hz, 1H), 7.16 (partially resolved dd, J=8.3, 5.6 Hz, 1H).

The corresponding hydrochloride salt was obtained as a colorless solidfrom an analogous preparation of the amine freebase (smaller scale), byaddition of ca. 2.5 equivalents HCl in dioxane (4M solution) to thedried chloroform extracts prior to concentration. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 2.84-3.07 (m, 2H), 3.25 (td, J=17.12, 7.67 Hz, 2H),3.91-4.09 (m, 1H), 6.94-7.06 (m, 1H), 7.08-7.15 (m, J=9.44, 9.15, 1.05,1.05 Hz, 1H), 7.28 (dd, J=8.20, 5.35 Hz, 1H), 8.40 (br. s., 3H).

Example III-11 (2S)- and (2R)-5-fluoro-2,3-dihydro-1H-inden-2-aminehydrochloride

Step 1: rac-(5-fluoro-2,3-dihydro-1H-inden-2-yl)benzyl carbamate

To a mixture of 5-fluoro-2,3-dihydro-1H-inden-2-amine (5.79 g; 38.3mmol; Example III-9 above) and satd Na₂CO₃ (200 mL) at room temperaturewas added benzyl chloroformate (6.9 mL; 46 mmol). The mixture wasstirred 1 h at room temperature and extracted with EtOAc (×3). Combinedorganics were washed (H₂O, brine), dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash chromatography (EtOAc/hexanes),affording the title compound as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.77 (m, 2H), 3.12 (m, 2H), 4.29 (app. sext., J=7.1 Hz, 1H),5.02 (s, 2H), 6.94 (m, 1H), 7.03 (partially resolved dd, J=9.2, ˜2.4 Hz,1H), 7.19 (partially resolved dd, J=8.2, 5.5 Hz, 1H), 7.28-7.40 (m, 5H),7.64 (d, J=6.8 Hz, 1H).

Step 2: Resolution of rac-(5-Fluoro-2,3-dihydro-1H-inden-2-yl)benzylcarbamate into [(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]benzyl carbamateand [(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]benzyl carbamate

rac-(5-Fluoro-2,3-dihydro-1H-inden-2-yl)benzyl carbamate was separatedinto individual enantiomers on an AD-H prep column (30 mm ID×25 mm, 5 μmparticle size) by supercritical fluid chromatography (MeOH/CO₂ 17:83, 90g/min total flow at 140 bar, 33° C.). Chromatographic bands eluting fromthe column were detected at 215 nm. Assignment of absoluteconfigurations for the enantiomers obtained above were made bycomparison of experimentally measured vibrational circular dichroism(VCD) spectra with the calculated (ab initio) VCD spectrum for[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]benzyl carbamate. Theearlier-eluting enantiomer from the chiral separation described abovewas found to have VCD bands of the same relative sign as the(S)-configuration model used for ab initio calculations, and thusassigned the (S)-configuration. In contrast, the latter-elutingenantiomer was found to was found to have VCD bands of the oppositerelative sign as the (S)-configuration model used for ab initiocalculations, and thus assigned the (R)-configuration.

Step 3: (S)- and (R)-5-fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride

The preparation of (S)-5-fluoro-2,3-dihydro-1H-inden-2-aminehydrochloride is given as representative. To a solution of[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]benzyl carbamate (2.26 g; 7.93mmol) in EtOAc/EtOH (40 mL ea) was added 10% Pd/C (0.85 g, wet, DeGussatype E101). The mixture was stirred under an atmosphere of H₂ for 5 hand filtered through a 0.45 μm PTFE membrane filter. HCl in dioxane (5mL of a 4M solution) was added to the filtrate and the whole wasconcentrated to dryness, affording the title compound as a tan solid. ¹HNMR (400 MHz, DMSO-d₆) δ 2.97 (m, 2H), 3.24 (m, 2H), 4.00 (m, 1), 7.01(m, 1H), 7.13 (partially resolved dd, J=9.2, ˜2.4 Hz, 1H), 7.28 (dd,J=8.4, 5.4 Hz, 1H), 8.40 (br. s, 2H). (M+H) 152, t_(R) 0.73 min (LC/MSmethod C). (R)-5-Fluoro-2,3-dihydro-1H-inden-2-amine hydrochloride wasprepared in an analogous fashion; ¹H NMR spectrum and LC/MS retentiontime were identical to those of the (S)-isomer.

Example III-12 rac 2-amino-2,3-dihydro-1H-indene-5-carbonitrilehydrochloride

Step 1: 1,1-Dimethylethyl (5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate

To a slurry of (5-bromo-2,3-dihydro-1H-inden-2-yl)amine hydrobromide(5.61 g; 19.1 mmol; prepared according to Prashad, M; Hu, B.; Har, D.;Repic, O.; Blacklock, T.; Acemoglub, M. Adv. Synth. Catal. 2001, 343(5), 461) in CH₂Cl₂ (40 mL) was added Et₃N (5.8 mL; 42 mmol) in oneportion. The mixture was stirred 15 min, (Boc)₂O (4.58 g; 21 mmol) wasadded in one portion and stirring was continued. After 2 h the whole wasadsorbed onto a minimal amount of silica gel and purified by flashchromatography (EtOAc/hexanes), affording 5.94 g of the title compoundas a colorless solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.39 (s, 9H), 2.73 (m,2H), 3.08 (m, 2H), 4.20 (app. sext, J=7.0 Hz, 1H), 7.14 (d, J=8.2 Hz,1H), 7.19 (br. d, J=6.8 Hz, 1H), 7.30 (partially resolved dd, J=8.0,˜1.9 Hz, 1H), 7.38 (m, 1H) ppm.

Step 2: 1,1-dimethylethyl (5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate

A flask charged with 1,1-dimethylethyl(5-bromo-2,3-dihydro-1H-inden-2-yl)carbamate (3.0 g, 9.26 mmol; step 1above), dppf (645 mg, 1.16 mmol), Pd₂ dba₃ (532 mg, 0.58 mmol), ZnCN₂(1.50 g, 12.8 mmol) and water in 50 mL DMF was evacuated/backfilled withnitrogen (×4), and stirred at 110° C. for 21 hours. Upon cooling, themixture was diluted with satd NH₄Cl and extracted with ethyl acetate.The organic extract was washed with (water 3×, brine), dried over MgSO₄and concentrated in vacuo. The residual oil was purified by flashchromatography (ethyl acetate/hexanes) affording title compound as anoff-white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (s, 1H), 7.45 (d, 1H,J=7.9 Hz), 7.28 (d, 1H, J=7.7 Hz), 4.69 (br.s, 1H), 4.47 (br. s, 1H),3.33-3.25 (m, 2H), 2.86-2.80 (m, 2H), 2.79 (s, 9H).

Step 3: 2-amino-2,3-dihydro-1H-indene-5-carbonitrile hydrochloride

To a solution of 1,1-dimethylethyl(5-cyano-2,3-dihydro-1H-inden-2-yl)carbamate (1.85 g, 7.18 mmol) indioxane (30 mL) at room temperature was added HCl in dioxane (18 mL of a4.0 M solution; 72 mmol). The mixture was stirred for ca. 18 hr anddiluted with ether. Solids were collected by filtration and rinsedthoroughly with ether, affording the title compound as a tan solid. ¹HNMR (400 MHz, methanol-d₄) δ ppm 7.65 (s, 1H), 7.59 (d, 1H, J=7.9 Hz),7.46 (d, 1H, J=7.9 Hz), 4.14 (m, 1H), 3.51-3.43 (m, 2H), 3.10-3.04 (m,1H).

Example III-13 rac 5-(methyloxy)-2,3-dihydro-1H-inden-2-aminehydrochloride

Step 1: (2Z)-5-(methyloxy)-1H-indene-1,2(3H)-dione 2-oxime

To a solution of 5-(methyloxy)-2,3-dihydro-1H-inden-1-one (1.0 g, 6.2mmol) in methanol (15 mL) at 40° C. was added n-butyl nitrite (0.8 mL,6.25 mmol) followed by conc HCl (0.6 mL). The reaction was stirred 30min, precipitated solid was collected by filtration, air-dried and usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.60(br.s, 2H) 3.86 (s, 3H) 6.99 (dd, J=8.54 Hz, 2.2 Hz, 1H) 7.12 (d, J=1.71Hz, 1H) 7.66 (d, J=8.55 Hz, 1H) 12.45 (s, 1H).

Step 2: 5-(methyloxy)-2,3-dihydro-1H-inden-2-amine hydrochloride

To a solution of (2Z)-5-(methyloxy)-1H-indene-1,2(3H)-dione 2-oxime(0.96 g, 5.02 mmol) in HOAc/conc H₂SO₄ (25/2 mL respectively) was added10% Pd/C (0.200 g, wet) and the mixture was hydrogenated under 50 psi H2for 7 h at room temperature using a Parr hydrogenation apparatus andfiltered over Celite (2×10 mL MeOH wash). The filtrate was partiallyconcentrated and basified ca. pH 12, and the whole was extracted withCH₂Cl₂ (2×100 mL). Combined organics were dried over Na₂SO₄, andconcentrated to ca. 100 mL. The remaining solution was sparged withanhyd HCl (ca. 1 min), aged 15 min and concentrated to dryness affordingthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.84-2.98 (m, 2H),3.09-3.24 (m, 2H), 3.75 (s, 3H), 3.92 (br. s, 1H), 6.73 (dd, J=8.3, 2.44Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 7.13 (d, J=8.1 Hz, 1H), 8.40 (br.s,2H).

Example III-14 rac 4-(methyloxy)-2,3-dihydro-1H-inden-2-aminehydrochloride

The title compound was prepared from4-(methyloxy)-2,3-dihydro-1H-inden-1-one according to the methoddescribed in example III-13 Steps 1-2 above. ¹H NMR (400 MHz, DMSO-d₆) δppm 2.84-2.98 (m, 2H), 3.10-3.27 (m, 2H), 3.75 (s, 3H), 3.95 (br.s, 1H),6.79 (d, J=8.1 Hz, 1H), 6.84 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.8 Hz, 1H),8.31 (br.s, 2H).

Example III-15 5,6-bis(methyloxy)-2,3-dihydro-1H-inden-2-aminehydrochloride

The title compound was prepared from5,6-bis(methyloxy)-2,3-dihydro-1H-inden-1-one according to the methoddescribed in example III-13 Steps 1-2 above. ¹H NMR (400 MHz, DMSO-d₆) δppm 2.84-2.98 (m, 2H), 3.10-3.27 (m, 2H), 3.75 (s, 3H), 3.95 (br.s, 1H),6.79 (d, J=8.1 Hz, 1H), 6.84 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.8, Hz, 1H),8.31 (br.s, 2H).

Example III-16 2-methyl-2,3-dihydro-1H-inden-2-amine hydrochloride

Step 1: methyl 2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate

To a solution of diisopropylamine (2.06 mL, 14.6 mmol) in THF (14 mL) at0° C. was a solution of n-butyl lithium (5.55 mL of a 2.5 M in solutionin hexanes; 14.6 mmol), dropwise over 15 min. Meanwhile, a solution of2-methyl-1-indanone (2.03 g, 13.9 mmol) in THF (10 mL) was prepared andcooled to −78° C. under N₂. After 30 minutes the above solution of LDAwas cooled to −78° C. and added to the above solution of indanone,dropwise over 15 min via double-ended needle. The mixture was stirred 30min and methyl cyanoformate (1.32 mL, 16.7 mmol) was added. The mixturewas stirred 40 minutes, gradually warming ca. to −20° C., quenched withsatd NH₄Cl and extracted with Et₂O (2×25 mL). Combined organics werewashed (brine), dried over Na₂SO₄ and concentrated in vacuo, affordingthe title compound which was used without further purification. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.52 (s, 3H), 3.00 (d, J=17.3 Hz, 1H), 3.67-3.73(m, 4H), 7.41 (t, J=7.57 Hz, 1H), 7.47 (m, 1H), 7.63 (m, 1H), 7.79 (d,J=7.57 Hz, 1H).

Step 2: methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate

A mixture of the methyl2-methyl-1-oxo-2,3-dihydro-1H-indene-2-carboxylate (2.04 g, 9.99 mmol)and 10% Pd/C (0.200 g; wet) in HOAc/conc H₂SO₄ (22/2 mL respectively)was hydrogenated under 50 psi H2 for 4 h using a Parr hydrogenationapparatus. The mixture was filtered through Celite (2×MeOH wash) and thefiltrate was partially concentrated in vacuo. The residue wasneutralized with satd Na₂CO₃ and the whole was extracted with EtOAc(2×25 mL). Combined organics were washed with brine, dried over Na₂SO₄and concentrated in vacuo affording the title compound. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.35 (s, 3H), 2.81 (d, J=15.6 Hz, 2H), 3.47 (d, J=15.6 Hz,2H), 3.71 (s, 3H), 7.12-7.23 (m, 4H).

Step 3: 2-Methyl-2,3-dihydro-1H-indene-2-carboxylic acid

To a solution of methyl 2-methyl-2,3-dihydro-1H-indene-2-carboxylate(1.80 g, 9.46 mmol) in THF/water/MeOH (4/1/1 mL respectively) was addedlithium hydroxide monohydrate (1.19 g, 28.4 mmol). The reaction mixturestirred at ambient temperature 4 h, acidified to pH 3 with 1 N HCl andextracted with Et₂O (2×25 mL). Combined organics were washed (water,brine), dried over Na₂SO₄ and concentrated in vacuo affording the titlecompound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.39 (s, 3H),2.83 (d, J=15.9 Hz, 2H), 3.50 (d, J=15.9 Hz, 2H), 7.12-7.23 (m, 4H).

Step 4: phenylmethyl (2-methyl-2,3-dihydro-1H-inden-2-yl)carbamate

To a solution of 2-methyl-2,3-dihydro-1H-indene-2-carboxylic acid (0.200g, 1.14 mmol) and triethylamine (0.17 mL, 1.2 mmol) in benzene (2 mL) at0° C. was added diphenyl phosphorylazide (0.257 g, 1.19 mmol). Themixture was stirred 15 min, benzyl alcohol (0.123 mL, 1.19 mmol) wasadded and the reaction was heated under reflux for 16 hours. Uponcooling, the mixture was diluted with 10% HCl and extracted with ethylacetate (2×25 mL). Combined organics were washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/hexanes) affording the title compound. ¹H NMR (400MHz, CDCl₃) δ ppm 1.55 (s, 3H), 2.98 (d, J=15.9 Hz, 2H), 3.28 (d, J=15.9Hz, 2H), 7.12-7.18 (m, 4H), 7.29-7.37 (m, 5H).

Step 5: (2-methyl-2,3-dihydro-1H-inden-2-yl)amine hydrochloride

A mixture phenylmethyl (2-methyl-2,3-dihydro-1H-inden-2-yl)carbamate(0.271 g; 0.963 mmol), and 10% Pd/C (0.050 g, wet) in EtOH (2 mL) of washydrogenated under 40 psi H₂ for 4 h at using a Parr hydrogenationapparatus and filtered over Celite. The filtrate was concentrated to anoil, dissolved in ethyl acetate, cooled to −70° C. and sparged withanhyd HCl until saturated. The mixture was stirred for 1 hour andconcentrated to dryness affording the title compound as a white solid.¹H NMR (400 MHz, methanol-d₄) δ ppm 1.56 (s, 3H), 3.17 (br.s, 4H),7.19-7.29 (m, 4H).

Compounds of Formula IV

Example IV-1 3-bromo-4-methylbenzamide

To a slurry of 3-bromo-4-methylbenzoic acid (2.53 g, 85% purity; 10mmol) in CH₂Cl₂ (20 mL) at 0° C., under N₂, was added oxalyl chloride(0.91 mL; 10.5 mmol), followed by dropwise addition of DMF (0.04 mL; 0.5mmol). The mixture was stirred 5 min at 0° C., 15 min at rt, and thenheated at reflux under N₂ for 1 h. The mixture was cooled, and pouredinto NH₄OH (30 mL; ca. 30% NH₃). Precipitated solids were collected byfiltration and purified by flash chromatography (EtOAc/hexanes),affording the title compound as a colorless solid. LC/MS (method A)t_(R) 2.05 min; m/z 214, 216 (M+H, Br isotopes).

The following were prepared by a procedure similar to Example IV-1, fromthe appropriate carboxylic acids.

TABLE B Synthesis of Compounds of Formula IV from benzoic acidsCharacterization Ex Structure/Name Data Comments IV-2

3-bromo-2-methylbenzamide LC/MS (method A) t_(R) 1.87 min; m/z 223, 225(M + H, Br isotopes) Note 1 IV-3

5-bromo-2-methylbenzamide LC/MS (method B) t_(R) 1.80 min; m/z 214, 216(M + H, Br isotopes) Note 1, 3 IV-4

4-bromo-3-methylbenzamide LC/MS (method A) t_(R) 2.06 min; m/z 214 ([M +H]⁺) Note 1, 2 IV-5

4-bromo-3-fluorobenzamide LC/MS (method A) t_(R) 1.88 min; m/z 218 ([M +H]⁺) Note 1, 2 IV-6

3-bromobenzamide LC/MS (method B) t_(R) 1.79 min; m/z 200, 202 (M + H,Br isotopes) Note 1, 4 IV-7

4-bromo-2-fluorobenzamide LC/MS (method A) t_(R) 1.72 min; m/z 218 (M +H). Notes 1, 2 Note 1 Chromatographic purification step omitted. Note 2Preparation of acid chloride using 4 equivalents of oxalyl chloride atroom temperature for 3 hours. Note 3 5-Bromo-2-methylbenzoic acid may beobtained commercially from various sources (e.g., Ryan Scientific, Inc.,Mt. Pleasant, SC, USA). Note 4 Acid activation with oxalyl chloride/DMFwas omitted; commercially available 3-bromobenzoyl chloride was used(Sigma-Aldrich, St. Louis, MO, USA).

Example IV-8 3-Bromo-5-chlorobenzamide

To a solution of 3-bromo-5-chlorobenzoic acid (2.88 g; 12.2 mmol;Note 1) and pyridine (1.04 mL; 12.8 mmol) in MeCN (100 mL) at roomtemperature was added (Boc)₂O (3.47 g; 15.9 mmol) in one portion. Themixture was aged 30 min, (NH₄)₂CO₃ was added in one portion. Afterstirring approximately 16 h at room temperature, volatiles were removedin vacuo. The residue was partitioned between EtOAc/water and the layerswere separated. The aqueous layer was extracted with EtOAc (×2),combined organics were washed (10% HCl, brine), dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(EtOAc/hexanes), affording the title compound as a colorless solid.LC/MS (method A) t_(R) 1.65 min; m/z 234, 236 (M+H, Br isotopes).

Note 1: 3-bromo-5-chlorobenzoic acid was obtained commercially fromBiofine International Inc., Blaine, Wash., USA.

The following were prepared by a procedure similar to Example IV-8 fromthe appropriate carboxylic acids.

TABLE C Compounds of Formula IV from benzoic acids and (NH₄)₂CO₃ ExStructure/Name Characterization Data Comments IV-9 

3-bromo-5- methylbenzamide LC/MS (method A) t_(R) 2.12 min; m/z 214, 216(M + H, Br isotopes) Note 1 Carboxylic acid from SALOR (Aldrich) IV-10

3-bromo-5- (trifluoromethyl) benzamide LC/MS (method B) t_(R) 2.38 min;m/z 268, 270 (M + H, Br isotopes) [M − H]⁻ Note 2 Carboxylic acid fromMatrix Scientific, Columbia, SC, USA IV-11

LC/MS (method B) t_(R) 1.43 min; m/z 201, 203 (M + H, Br isotopes) Note2 IV-12

4-chloro-2- pyridinecarboxamide LC/MS (method B) t_(R) 1.36 min; m/z 157Note 2 IV-13

3-bromo-2- chlorobenzamide LC/MS (method A) t_(R) 1.65 min; m/z 234, 236(M + H, Br isotopes) Note 3 Note 1 Pyridine was added to solution ofcarboxylic acid and (Boc)₂O. Note 2 Chromatographic purification stepomitted. Note 3 3-Bromo-2-chlorobenzoic acid may be obtained from thecommercially available 3-bromo-2-chlorotoluene according to theprocedure of Liedholm, B. Acta Chem. Scand. B Org. Chem. Biochem. 1984,B38(8), 713.

Example IV-14 3-bromo-2-methoxybenzamide

Step 1: 3-bromo-2-hydroxybenzonitrile

To a solution of o-cyanophenol (0.595 g; 5.00 mmol) and diisopropylamine(0.060 mL; 0.40 mmol) in PhMe (50 mL) at 70° C. was added NBS (0.980 g;5.50 mmol) in one portion. The mixture was stirred 2 h, an additionalportion of NBS (0.089 g; 0.5 mmol) was added and heating continued untildisappearance of starting material was observed (TLC). The mixture wascooled, diluted with EtOAc washed (water, brine), dried over Na₂SO₄ andconcentrated in vacuo. Attempted resolution of the two reaction productsby flash chromatography (EtOAc/hexanes), was unsuccessful; thus themixture of products was dissolved in DMF (10 mL), K₂CO₃ (2.07 g; 15.0mmol) and MeI (0.47 mL; 7.5 mmol) were added and the mixture was stirredovernight at room temperature. The mixture was poured into water andextracted with Et₂O (×3). Combined organics were washed (water, brine),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (EtOAc/hexanes), affording the title compound as acolorless solid. ¹H NMR (400 MHz, DMSO-d6) δ ppm 3.97 (s, 3H), 7.26(app. t, J=7.9 Hz, 1H), 7.86 (dd, J=7.8, 1.5 Hz, 1H), 8.01 (dd, J=8.1,1.5 Hz, 1H). The product obtained above was combined with that of asimilar reaction wherein N-methylbenzylamine (0.08 equiv) wassubstituted for the above diisopropylamine catalyst.

Step 2: 3-bromo-2-methoxybenzamide

To a slurry of 3-bromo-2-methoxybenzamide (0.933 g; 4.40 mmol) and K₂CO₃(0.304 g; 2.2 mmol) in DMSO (10 mL) at 0° C. was added H₂O₂ (0.5 mL of a30 wt % solution; ˜4.8 mmol), dropwise over 2 min. The cooling bath wasremoved, the mixture was stirred at room temperature 3 days, poured intowater and precipitated solid was collected by filtration. The filtratewas extracted 3×EtOAc, combined organics were washed (water, brine),dried over Na₂SO₄ and concentrated in vacuo. The residue was combinedwith the above precipitated solid and the whole was purified by flashchromatography (EtOAc/hexanes), affording the title compound as acolorless solid. LC/MS (method A) t_(R) 1.88 min; m/z 230, 232 (M+H, Brisotopes).

The following were prepared from the appropriate benzonitriles by aprocedure similar to Example IV-14, Step 2.

TABLE D Compounds of Formula IV via the corresponding benzonitrile ExStructure/Name Characterization Data Comments IV-15

LC/MS (method A) t_(R) 1.78 min; m/z 214, 216 (M + H, Br isotopes)Chromatographic purification step omitted IV-16

LC/MS (method B) t_(R) 1.73 min; m/z 218, 220 (M + H, Br isotopes)Nitrile from Oakwood Products, Inc. West Columbia, SC, USA. IV-17

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.68 (br. s, 1H), 7.69 (ddd, J = 9.6,1.2 Hz, 2H, overlapping 7.68), 7.75 (ddd, J = 8.2, 2.5, 1.6 Hz, 1H),7.92 (partially resolved dd, J = 1.4 Hz, 1H), 8.16 (br. s., 1H) Nitrilefrom Matrix Scientific, Columbia, SC, USA.

Example IV-18 2-Bromo-1,3-thiazole-4-carboxamide

Step 1: 2-Bromo-1,3-thiazole-4-carboxylic Acid

A mixture of methyl 2-bromo-1,3-thiazole-4-carboxylate (4.2 g, 18.9mmol), THF (120 mL) and 1N lithium hydroxide (50 mL) was heated at 70°C. for 1 h. The organic solvent was removed in vacuo. The residualaqueous solution was cooled to 0-5° C. and acidified to pH1 with 1N HClsolution. The tile compound was obtained by filtration, as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.43 (s, 1H) 13.30 (s, 1H).

Step 2: 2-Bromo-1,3-thiazole-4-carboxamide

To a suspension of 2-bromo-1,3-thiazole-4-carboxylic acid (3.82 g, 18.4mmol) and a catalytic amount of DMF in CH₂Cl₂ (100 mL) at 0° C. wasslowly added thionyl chloride (14 mL of a 2M solution in CH₂Cl₂). Theresulting mixture was stirred for 12 h at the room temperature and thenheated to reflux for 1 h. The mixture was concentrated to dryness invacuo. The white solid obtained was taken up in ethyl acetate, added toa pre-cooled (0° C.) 9-10% aqueous ammonium hydroxide solution (90 ml)and stirred for 1 h at 0° C. The organic layer was separated and theaqueous phase was extracted twice with ethyl acetate. The combined ethylacetate solution was washed with brine, dried over magnesium sulfate andconcentrated in vacuo, affording the title compound was obtained as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.60 (s, 1H), 7.82 (s,1H), 8.22 (s, 1H).

Example IV-1 4-iodo-3-(methyloxy)benzamide

Step 1: methyl 4-iodo-3-(methyloxy)benzoate

To a solution of 3-hydroxy-4-iodobenzoic acid (3.0 g, 0.011 mol) inacetone (50 mL) was added in one portion potassium carbonate (3.9 g,0.028 mol). Dimethyl sulfate (3.5 g, 0.028 mol) was added dropwise andthe mixture was heated at reflux overnight. The mixture was concentratedin vacuo and the residue was partitioned between ethyl acetate andaqueous saturated sodium bicarbonate solution. The organic phase waswashed with brine, dried over sodium sulfated and concentrated in vacuoto give methyl 4-iodo-3-(methyloxy)benzoate as a yellow oil. ¹H NMR(DMSO-d₆) δ ppm 3.83 (s, 3H, Me), 3.87 (s, 3H, Me), 7.30 (dd, J=8.0, 1.8Hz, 1H, Ar), 7.40 (d, J=1.7 Hz, 1H, Ar), 7.92 (d, J=8.0 Hz, 1H, Ar).

Step 2: 4-iodo-3-(methyloxy)benzoic acid

A mixture of methyl 4-iodo-3-(methyloxy)benzoate (3.25 g, 0.011 mol),sodium hydroxide (0.48 g, 0.012 mol) and water (30 mL) in methanol (30mL) was heated in an oil bath at 65° C. for 3 hr. The mixture wasconcentrated in vacuo to remove the methanol and the aqueous residue waschilled in an ice bath. Concentrated aqueous hydrogen chloride was addeduntil the pH was acidic and the mixture was stirred at ice bathtemperature. The resulting solid was filtered, washed with water anddried to give 4-iodo-3-(methyloxy)benzoic acid as a white solid, usedwithout further purification. LC/MS (method A) t_(R) 2.35 min; m/z 279(M+H).

Step 3: 4-iodo-3-(methyloxy)benzamide

Oxalyl chloride (5.1 g, 0.04 mol) was added dropwise to a mixture of4-iodo-3-(methyloxy)benzoic acid (2.9 g, 0.01 mol) and DMF (3 drops) indichloromethane (60 mL) at room temperature. After 3 hr, the mixture wasconcentrated in vacuo. The residue was dissolved in dichloromethane (30mL) and this solution was added dropwise to concentrated ammoniumhydroxide (40 mL) at ice bath temperature. The mixture was stirred atroom temperature overnight. The mixture was partially concentrated invacuo and the aqueous residue was extracted with ethyl acetate. Theorganic extract was washed (satd Na₂CO₃, brine), dried with sodiumsulfate and concentrated in vacuo to give 4-iodo-3-(methyloxy)benzamideas a white solid, used without further purification. LC/MS (method A)t_(R) 1.95 min; m/z 278 (M+H).

Example IV-20 4-(aminocarbonyl)-2-chlorophenol trifluoromethanesulfonate

Step 1: 4-(aminocarbonyl)-2-chlorophenyl 1,1-dimethylethyl carbonate

To a solution of 3-chloro-4-hydroxybenzoic acid (4.0 g, 0.022 mol) andpyridine (0.8 mL) in acetonitrile (50 mL) was added di-tert-butyldicarbonate (9.6 g, 0.044 mol) in one portion followed by ammoniumbicarbonate (3.5 g, 0.044 mol) in one portion and the mixture wasstirred at ambient temperature for 18 hr. The reaction mixture wasconcentrated in vacuo and the residue was partitioned between ethylacetate and water. The ethyl acetate phase was washed with 5% aqueoussodium bicarbonate, 0.1N HCl and brine. The organic phase was dried oversodium sulfate, filtered and concentrated in vacuo to give4-(aminocarbonyl)-2-chlorophenyl 1,1-dimethylethyl carbonate as aviscous yellow oil, used without further purification. LC/MS (method A)t_(R) 2.25 min; m/z (M+H) 272.

Step 2: 3-chloro-4-hydroxybenzamide

A mixture of 4-(aminocarbonyl)-2-chlorophenyl 1,1-dimethylethylcarbonate (6.86 g, 0.025 mol) and 4N HCl in dioxane (50 mL) in dioxane(30 mL) was heated at reflux for 4 hr. The reaction mixture was cooled,and precipitated solid was collected by filtration affording3-chloro-4-hydroxybenzamide as a white solid, used without furtherpurification. LC/MS (method E) t_(R) 0.88 min; m/z 172 (M+H).

Step 3: 4-(aminocarbonyl)-2-chlorophenyl trifluoromethane sulfonate

To a mixture of 3-chloro-4-hydroxybenzamide (3.3 g, 0.019 mol) andpyridine (3.0 g, 0.038 mol) in dichloromethane (30 mL) at ice bathtemperature was added dropwise trifluoromethanesulfonic anhydride (5.9g, 0.021 mol). The mixture was allowed to come to ambient temperatureovernight. The reaction mixture was washed (water, brine), dried bypassing through a plug of sodium sulfate and concentrated in vacuoaffording 4-(aminocarbonyl)-2-chlorophenyl trifluoromethane sulfonate asa pale yellow solid, used without further purification. LC/MS (method B)t_(R) 2.48 min; m/z 304 (M+H).

Compounds of Formula IV (Heterocycles) Example IV-212-(3-Bromophenyl)-1H-imidazole

Step 1: Methyl 3-bromobenzenecarboximidoate hydrochloride

A solution of m-bromobenzonitrile (1.82 g; 10 mmol) in MeOH (20 mL) at0° C. was sparged with HCl gas for 30 min, the reaction flask wasstoppered and aged in a refrigerator (ca. 5° C.) for 3 h. The mixturewas sparged with N₂ to remove excess HCl, concentrated in vacuo (2×PhMechase) and dried under high vacuum ca. 45 min, affording the titlecompound as a colorless solid which was used directly for Step 2 below.LC/MS (method A) t_(R) 0.81 min, m/z 214, 216 (M+H, Br isotopes).

Step 2: N-[2,2-bis(ethyloxy)ethyl]-3-bromobenzene carboximidamide

To a solution of methyl 3-bromobenzenecarboximidoate hydrochloride (Step1 above) in MeOH (10 mL) at 0° C. was added[2,2-bis(ethyloxy)ethyl]amine (1.74 mL; 12 mmol) in one portion and themixture was gradually warmed to room temperature (overnight). Themixture was concentrated in vacuo, partitioned between CH₂Cl₂/1M NaOHand the layers were separated. The aqueous layer was extracted withCH₂Cl₂ (×2), combined organics were washed (H₂O, brine), dried overNa₂SO₄, filtered and concentrated in vacuo affording the title compoundas a light brown oil which was used directly for Step 3 below. LC/MS(method A) t_(R) 1.25 min, m/z 315, 317 (M+H, Br isotopes, 4%), 223, 225(M+H−2EtOH, Br isotopes, 100%).

Step 3: 2-(3-Bromophenyl)-1H-imidazole

A solution of N-[2,2-bis(ethyloxy)ethyl]-3-bromobenzenecarboximidamide(2.85 g; 9.04 mmol; Step 2 above) in HCO₂H (15 mL) was heated at 80° C.for 1 h and concentrated in vacuo (2×PhMe chase). The residue waspurified by flash chromatography (MeOH/NH₄OH/CH₂Cl₂), affording thetitle compound as a light pink solid. LC/MS (method A) t_(R) 1.19 min,m/z 223, 225 (M+H, Br isotopes).

Example IV-22 2-(4-bromophenyl)-1H-imidazole

The title compound was prepared from p-bromobenzonitrile as describedfor the preparation Example IV-21, with the exception that purificationof the title compound consisted of a combination of recrystallization(i-PrOH) and flash chromatography (EtOAc/hexanes). LC/MS (method A)t_(R) 1.25 min, m/z 223, 225 (M+H, Br isotopes).

Example IV-233-(3-Bromophenyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazoleand5-(3-bromophenyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazole

Step 1: 3-(3-Bromophenyl)-1H-1,2,4-triazole

To a slurry of methyl 3-bromobenzenecarboximidoate hydrochloride(example IV-21 Step 1; 0.541 g; 2.18 mmol) in pyridine (3 mL) at 0° C.was added a solution of formic hydrazide (0.157 g; 2.62 mmol). The flaskwas stoppered and gradually warmed to room temperature (overnight) andpoured into water (˜20 mL). Precipitated solid was collected byfiltration and the filtrate was extracted with EtOAc (×3). Combinedextracts were washed (water, brine), dried over Na₂SO₄, concentrated invacuo. The residue obtained was combined with the above precipitate, andthe whole was purified by flash chromatography (EtOAc/hexanes),affording the title compound as a colorless solid. LC/MS (method A)t_(R) 2.49 min, m/z 224, 226 (M+H, Br isotopes).

Step 2:3-(3-Bromophenyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazoleand 5(3-bromophenyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazole

To a slurry of hexanes-washed NaH (0.085 g of a 60 wt % suspension inmineral oil; ˜2.1 mmol) in DMF (3 mL) at 0° C. was added a solution of3-(3-bromophenyl)-1H-1,2,4-triazole (0.238 g; 1.06 mmol; Step 1 above)in DMF (1 mL), dropwise over 2 min. The mixture was stirred 30 min andSEM-Cl (0.22 mL; 1.27 mmol) was added, dropwise. The mixture wasgradually warmed to room temperature (overnight), poured into water andextracted with EtOAc (×3). Combined organics were washed (water, brine),dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash chromatography (EtOAc/hexanes), affording two regioisomericN-protected triazoles. The earlier-eluting regioisomer was a colorlessgum; the later-eluting regioisomer was a colorless, waxy solid (ratio˜2:5 earlier:later). Earlier-eluting isomer ¹H NMR (400 MHz, CDCl₃) δppm 0.02 (s, 9H), 0.95-1.05 (m, 2H), 3.77-3.86 (m, 2H), 5.51 (s, 2H),7.39 (t, J=7.94 Hz, 1H), 7.65 (ddd, J=8.07, 2.01, 0.98 Hz, 1H), 7.89(ddd, J=7.71, 1.65, 0.98 Hz, 1H), 7.97 (s, 1H), 8.12 (app. t, J=1.87 Hz,1H). Later-eluting isomer 1H NMR (400 MHz, CDCl₃) d ppm 0.01 (s, 9H),0.93-1.00 (m, 2H), 3.66-3.73 (m, 2H), 5.53 (s, 2H), 7.33 (t, J=7.94 Hz,1H), 7.54 (ddd, J=7.94, 2.05, 1.07 Hz, 1H), 8.06 (ddd, J=7.76, 1.52,1.07 Hz, 1H), 8.27 (s, 1H), 8.31 (app. t, J=1.78 Hz, 1H).

Example IV-24 [3-(3-Bromophenyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate

Step 1: 3-(3-Bromophenyl)-1H-1,2,4-triazole (Alternate Preparation)

A slurry of 3-bromobenzamide (77.4 g; 387 mmol) in DMF-DMA (150 mL) wasprepared at room temperature and heated to 80° C. for 5 h. The mixturewas cooled, poured into ice water (˜2 L) and stirred at room temperature2 h. Precipitated solid was collected by filtration and washed withwater (3×500 mL) and hexanes (2×200 mL), and the cake was air-dried onthe filter. The above solid was added to a solution of hydrazinemonohydrate (18.0 mL; 370 mmol) in acetic acid (500 mL) at roomtemperature (internal temp RT→˜40° C. during addition). The mixture wasstirred 5 min and heated to 90° C. for 90 min. The mixture was cooled,and partially concentrated in vacuo to approximately 100 mL. The mixturewas poured into ice water (˜3 L) and stirred 1 h. Precipitated solid wascollected by filtration, washed with water and the cake was air-dried onthe filter overnight. The solid was recrystallized from benzene,affording the title compound as a colorless solid. LC/MS (method E)t_(R) 0.61 min, m/z 224, 226 (M+H Br isotopes).

Step 2: [3-(3-Bromophenyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate

A slurry of 3-(3-bromophenyl)-1H-1,2,4-triazole (58.5 g; 261 mmol; Step1 above), anhydrous K₂CO₃ (43.2 g; 313 mmol), and chloromethylpivalate(45 mL; 313 mmol) in dry MeCN (250 mL) was heated to 80° C. (Note 1) for1 hour. The mixture was cooled, solid was collected by filtration andthe filtrate was concentrated in vacuo. Residue from the filtaret wascombined with the filtered solid and the whole was stirred with waterapproximately 20 minutes. Solid was collected by filtration, washed withwater (×3) and recrystallized from MeOH/water, affording the titlecompound as a colorless solid. LC/MS (method E) t_(R) 0.88 min, m/z 338,340 (M+H, Br isotopes).

The following were prepared from the appropriate benzamides by aprocedure similar to Example IV-25.

TABLE E Compounds of Formula IV from the corresponding benzamide ExStructure/Name Characterization Data Comments IV-26

LC/MS (method B) t_(R) 2.75 min, m/z 356 (79Br), 358 (Br isotopes) Note1, 2, 3 DMF used as solvent for Step 2. Used IV-16 benzamide IV-27

LC/MS (method A) t_(R) 2.85 min, m/z 352 (79Br), 354 (Br isotopes) Note1, 2, 3 Used IV-2 benzamide IV-28

LC/MS (method A) t_(R) 2.72 min, m/z 372 (79Br), 374 (Br isotopes) Note1, 2, 3 Used IV-13 benzamide IV-29

LC/MS (method A) t_(R) 2.89 min, m/z 235 (79Br), 237 (Br isotopes) Note4 IV-30

1H NMR (400 MHz, CDCl₃) δ ppm 1.09- 1.28 (s, 9H), 6.06 (s, 2H), 7.57 (d,J = 8.55 Hz, 2H), 7.98 (d, J = 8.55 Hz, 2H), 8.35 (s, 1H) Note 1, 2IV-31

1H NMR (400 MHz, CDCl₃) δ ppm 1.18 (s, 9H), 2.45 (s, 3H), 6.06 (s, 2H),7.59 (d, J = 8.30 Hz. 1H), 7.78 (dd, J = 8.06, 1.71 Hz, 1H), 7.99 (s,1H), 8.34 (s, 1H) Note 1, 2 Used IV-4 benzamide IV-32

(M + H) 356, (Br isotopes) 358, t_(R) 0.91 min LC/MS (method B, gradienttime = 1.5 min) Note 1, 2, 3 Used IV-5 benzamide Note 1 In some cases,benzamide adducts with DMF-DMA (step 1) were more conveniently isolatedby solvent extraction after pouring the reaction mixture into waterrather than recrystalliztion. Note 2 N—H triazole product of step 1 wasused directly for Step 2 without recrystallization. Note 3 N-alkylatedtriazole product of Step 2 was purified by flash chromatography(EtOAc/hexanes) Note 4 Step 2 only (N-alkylation); Cs₂CO₃ wassubstituted for K₂CO₃. 5-(3-bromophenyl)-1H-pyrazole may be obtainedfrom commercial sources (e.g., Sigma-Aldrich, St. Louis, MO, USA).

Example IV-33 [4-(3-bromophenyl)-1H-1,2,3-triazol-1-yl]methyl2,2-dimethylpropanoate

To a mixture of 1-bromo-3-ethynylbenzene (0.430 g; 2.38 mmol; Note 1),and azidomethyl 2,2-dimethylpropanoate (0.391 g; 2.49 mmol; Note 2) int-BuOH/water (3.5/3.0 mL respectively) at room temperature was added asolution of CuSO₄.5H₂O in water (0.030 g/0.5 mL), followed by sodiumascorbate (0.141 g; 0.71 mmol) in one portion. The mixture was stirred25 h at room temperature, diluted with water and extracted with EtOAc(×3). Combined organics were washed (5% NH₄OH, water, brine), dried overNa₂SO₄ and concentrated in vacuo affording the title compound as a tansolid which was used without further purification. LC/MS (method B) 2.77min, m/z 338, 340 (M+H, Br isotopes).

-   Note 1 1-Bromo-3-ethynylbenzene may be obtained according to the    procedure of Wettergren, J; Minidis, A. Tetrahedron. Lett. 2003,    44(41), 7611.-   Note 2 Azidomethyl 2,2-dimethylpropanoate may be obtained according    to the procedure of Loren, J; Krasiński, A.; Fokin, V.;    Sharpless, K. B. Synlett 2005, 18, 2847.

Example IV-34 3-(3-bromophenyl)-5-isoxazolamine

To a solution of 3-(3-bromophenyl)-3-oxopropanenitrile (1.12 g; 5.00mmol; Note 1) in EtOH (20 mL) was added a solution of hydroxylaminehydrochloride (1.74 g; 25 mmol) and NaOAc (2.46 g; 30 mmol) in water (20mL). The mixture was heated under reflux for 1 h, cooled andconcentrated in vacuo. The residue was slurried in 1N NaOH and extractedwith Et₂O (×1). The organic layer was washed (water, brine), dried overNa₂SO₄ and concentrated in vacuo affording the title compound as a paleyellow solid which was used without further purification. LC/MS (methodB) 2.21 min, m/z 239, 241 (Br isotopes).

Example IV-35 1-(3-bromophenyl)-1,3-dihydro-2H-imidazol-2-one

A solution of 1-bromo-3-isocyanatobenzene (1.0 mL, 8.01 mmol) and[2,2-bis(methyloxy)ethyl]amine (0.86 mL, 8.01 mmol) in CH₂Cl₂ (15 mL)was stirred at room temperature for 16 hr. The solution was concentratedin vacuo and the residue taken up in a mixture of CH₃CN (10 mL) and H₂O(3 mL). TFA (3 mL) was added and the solution stirred at roomtemperature for 4 hr. The solution was concentrated in vacuo, theresidue taken up in EtOAc then washed with satd NaHCO₃, H₂O, and brine.The organics were then dried over Na₂SO₄, concentrated in vacuo and theresidue recrystallized from EtOAc to give1-(3-bromophenyl)-1,3-dihydro-2H-imidazol-2-one as a white solid. 1H NMR(400 MHz, DMSO-d₆) δ ppm 6.60 (d, J=3.0 Hz, 1H), 7.03 (d, J=3.0 Hz, 1H),7.34-7.36 (m, 2H); 7.70-7.72 (m, 1H), 8.06 (s, 1H), 10.39 (br s, 1H).

Intermediate IV-36:4-(3-bromophenyl)-2-(triphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

Step 1: 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

A mixture of 3-bromoaniline (1.0 mL, 9.18 mmol), methylhydrazinocarboxylate (788 mg, 8.75 mmol), triethyl orthoformate (0.96mL, 8.75 mmol), and TsOH (25 mg) in MeOH (20 mL) was stirred at 65° C.for 3 hr. After cooling to room temperature, NaOMe (1.47 g, 26.2 mmol)was added and the mixture stirred at room temperature for 16 hr. Afterconcentration in vacuo the residue was taken up in EtOAc and H₂O thenacidified with 1N HCl. The aqueous phase was extracted with EtOAc andthe combined organics washed with H₂O then extracted twice with 1N NaOH.Combined NaOH extracts were acidified with conc. HCl and aged 5 min.Resulting solids were collected by filtration, washed with H₂O and driedto give 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one as a whitesolid. 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.42-7.46 (m, 1H), 7.53 (d, J=7.8Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 8.43 (s, 1H), 12.03 (s,1H).

Step 2:4-(3-bromophenyl)-2-(triphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

A mixture of 4-(3-bromophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (250mg, 1.04 mmol) and NaH (50 mg of a 60% dispersion in mineral oil, 1.25mmol) in DMF (3 mL) was stirred at room temperature for 30 min. To thesolution was added 1,1′,1″-(chloromethanetriyl)tribenzene (305 mg, 1.09mmol) and the mixture stirred at room temperature for 4 hr. The reactionmixture was diluted with EtOAc, washed with H₂O and brine, dried overNa₂SO₄ then concentrated in vacu. The residue was purified by silica gelchromatography (EtOAc/Hexanes) to give4-(3-bromophenyl)-2-(triphenylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-oneas a pale yellow foam. ¹H NMR (400 MHz, DMSO-d6) δ 7.22-7.31 (m, 15H),7.40-7.42 (m, 1H), 7.51 (d, J=7.8 Hz, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.90(s, 1H), 8.60 (s, 1H).

Intermediate IV-37:1-(3-bromophenyl)-3-(triphenylmethyl)-2,4-imidazolidinedione

Step 1: 1-(3-bromophenyl)-2,4-imidazolidinedione

A solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and chloroacetylisocyanate (0.780 mL, 9.18 mmol) in dioxane (100 mL) was stirred at roomtemperature for 2 hr. Dioxane (50 mL) and DBU (3.40 mL, 23.0 mmol) wereadded and the solution stirred at room temperature for 16 hr. Thesolution was concentrated in vacuo and the residue taken up in EtOAc andH₂O. The mixture was then acidified with 1N HCl, then the aqueous phaseextracted with EtOAc. The combined organics were then washed with H₂Oand brine and dried over Na₂SO₄. The solution was concentrated in vacuoand the residue recrystallized from EtOAc/hexanes to give1-(3-bromophenyl)-2,4-imidazolidinedione as a tan solid. 1H NMR (400MHz, DMSO-d₆) δ ppm 4.42 (s, 2H), 7.24-7.30 (m, 2H), 7.50-7.52 (m, 1H),7.87 (s, 1H), 11.27 (s, 1H).

Step 2: 1-(3-bromophenyl)-3-(triphenylmethyl)-2,4-imidazolidinedione

The trityl protection to render the title compound was performed in amanner similar to that described in the preparation of IV-36 Step 2. ¹HNMR (CDCl₃) δ ppm 4.20 (s, 2H), 7.17-7.22 (m, 4H), 7.25-7.28 (m, 8H),7.46-7.48 (m 6H), 7.79 (s, 1H).

Intermediate IV-38: 1-(3-bromophenyl)-2-imidazolidinone

1-Chloro-2-isocyanatoethane (1.18 mL, 13.8 mmol) was added dropwise to asolution of 3-bromoaniline (1.5 mL, 13.8 mmol) in DMF (30 mL) at 0° C.then stirred at room temperature for 16 hr, then 70° C. for 2 hr. Thesolution was cooled to room temperature and 1-chloro-2-isocyanatoethane(0.40 mL, 4.69 mmol) was added. After stirring at room temperature for 2hr, the solution was diluted with DMF (120 mL), cooled to 0° C. and NaH(660 mg, 60% dispersion in mineral oil, 16.5 mmol) added in portions.The mixture was stirred at room temperature for 64 hr, then diluted withEtOAc. After washing with H₂O three times then brine the solution wasdried over Na₂SO₄, concentrated in vacuo and the residue purified bysilica gel chromatography (EtOAc/hexanes) to give1-(3-bromophenyl)-2-imidazolidinone as a white solid. 1H NMR (400 MHz,CDCl₃) δ ppm 3.56-3.62 (m, 2H), 3.88-3.92 (m, 2H), 5.20 (br s, 1H),7.15-7.20 (m, 2H), 7.49-7.51 (m, 1H), 7.71 (s, 1H).

Intermediate IV-39: 2-(3-bromophenyl)-1,2,5-thiadiazolidine 1,1-dioxide

A solution of SO₂Cl₂ (12.6 mL, 0.155 mol) and 2-chloroethylaminehydrochloride (3.0 g, 25.9 mmol) in CH₃CN (100 mL) was stirred at 75° C.for 16 hr. The solution was concentrated and the residue dried in vacuo.The residue was then extracted with two 15 mL portions of Et₂O and thecombined washes then added dropwise to a solution of 3-bromoaniline(1.70 mL, 15.5 mmol) and TEA (7.20 mL, 51.7 mmol) in Et₂O (15 mL) at−78° C. After stirring at room temperature for 16 hr, the mixture wasdiluted with EtOAc then washed with H₂O and brine, dried over Na₂SO₄ andconcentrated. To the residue was added DMSO (100 mL) and K₂CO₃ (3.60 g,26.0 mmol). After stirring at room temperature for 2 hr the mixture waspoured into H₂O (500 mL), extracted twice with EtOAc and the combinedorganics washed with H₂O and brine then concentrated. The residue wasrecrystallized from EtOAc/hexanes to give2-(3-bromophenyl)-1,2,5-thiadiazolidine 1,1-dioxide as a light brownsolid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 3.48-3.49 (m, 2H), 3.82-3.85 (m,2H), 7.15 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.29-7.33 (m, 2H),7.85 (br s, 1H).

Intermediate IV-40: 2-(3-bromophenyl)isothiazolidine 1,1-dioxide

To a solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and TEA (2.60 mL,18.5 mmol) in CH₂Cl₂ (20 mL) was added 3-chloro-1-propanesulfonylchloride (1.40 mL, 11.5 mmol) at 0° C. After stirring at roomtemperature for 16 hr, 3-chloro-1-propanesulfonyl chloride (1.40 mL,11.5 mmol) and TEA (2.6 mL, 18.5 mmol) was added and the solutionstirred at room temperature for 2 hr. The solution was then washed withHCl (1.0 N, aq) and brine, dried over Na₂SO₄ then concentrated in vacuo.The residue was then taken up in DMF (40 mL) and DBU (4.10 mL, 27.6mmol) was added. The mixture was stirred at room temperature for 64 hr,diluted with EtOAc, then washed with 1N HCl and brine then concentrated.The residue was purified by silica gel chromatography (EtOAc/hexanes) togive 2-(3-bromophenyl)isothiazolidine 1,1-dioxide as an off-white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 2.50-2.54 (m, 2H), 3.37 (t, J=7.5 Hz, 2H),3.74 (t, J=7.5 Hz, 2H), 7.22-7.24 (m, 3H), 7.33 (s, 1H).

Compounds of Formula V

Example V-1 (5-bromo-2-thienyl)methyl][2-(3-fluorophenyl)ethyl]amine

To a 100 mL round bottom flask was added 5-bromo-2-thiophenecarbaldehyde(0.24 mL, 2 mmol), [2-(3-fluorophenyl)ethyl]amine (0.29 mL, 2.2 mmol),HOAc (0.12 mL, 1 mmol), sodium triacetoxyborohydride (1.2 g, 6 mmol) and1,2-dichloroethane (10 mL). The reaction was stirred overnight at roomtemperature, quenched with H₂O, and extracted with CH₂Cl₂ three times.The mixture was washed with brine, dried with MgSO₄ and concentratedunder reduced pressure. The crude material was purified by silica gelcolumn chromatography (ethyl acetate/hexane) affording the titlecompound. LC/MS (method A) t_(R) 1.54 min; m/z 315 (M+H).

The following examples were prepared from the appropriate heteroaromaticaldehydes and amines using a procedure similar to Example V-3.

TABLE F Compounds of Formula V from the corresponding heteroaromaticaldehyde Ex Structure/Name Characterization Data Comments V-2

LC/MS (method A) t_(R) 1.37 min; m/z 302, 304 (M + H, Br isotopes) V-3

LC/MS (method A) t_(R) 1.35 min; m/z 262, 264 (M + H, Br isotopes) V-4

LC/MS (method A) t_(R) 1.26 min; m/z 262, 264 (M + H, Br isotopes) V-5

LC/MS (method A) t_(R) 1.30 min, m/z 302, 304 (M + H, Br isotopes) V-6

LC/MS (method A) t_(R) 1.47 min; m/z 314, 316 (M + H, Br isotopes) V-7

LC/MS (method A) t_(R) 1.59 min; m/z 303, 305 (M + H, Br isotopes) amine= Ex. III-1

Example V-8 1,1-dimethylethyl{2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl) carbamate

Step 1: [(4-Bromophenyl)oxy]acetonitrile

A mixture of p-bromophenol (2.61 g; 15.1 mmol), bromoacetonitrile (1.11mL; 15.9 mmol), and Cs₂CO₃ (7.40 g; 22.7 mmol) in anhyd MeCN (25 mL) washeated at 80° C., under N₂ overnight. The mixture was cooled, filteredthrough a pad of Celite and concentrated in vacuo. The residue wasdissolved in a minimal amount of EtOAc/hexanes and filtered through ashort pad of silica gel (EtOAc/hexanes eluent), affording the titlecompound as a colorless, waxy solid which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 4.75 (s, 2H), 6.88 (m, 2H), 7.46(m, 2H).

Step 2: {2-[(4-Bromophenyl)oxy]ethyl}amine

To a solution of [(4-bromophenyl)oxy]acetonitrile (3.07 g; 14.5 mmol;step 1 above) in anhyd THF (10 mL) at 0° C. was added BH₃.DMS (18.1 mLof a 2M solution in THF; 36.2 mmol), dropwise over 5 min. The mixturewas heated under reflux for 1.5 h, cooled, and 2M HCl (ca. 50 mL) wasslowly added. The acidic mixture was extracted with Et₂O (×2) and theextracts set aside. NaOH pellets were added to the aqueous residue untilca. pH 14, and the whole was extracted with Et₂O (×3). Combined extractsof the basic mixture were washed (brine), dried over Na₂SO₄, andconcentrated in vacuo, affording the first batch of title compound as apale yellow liquid. The reserved Et₂O extracts (from acidic mixture)were concentrated in vacuo, the residue was heated at near reflux in 15wt % NaOH (aq) for 15 min, cooled, and extracted with CH₂Cl₂ (×3).Combined organics were washed (brine) and concentrated in vacuo. Theresidue was slurried in 4M HCl and insoluble material was removed byfiltration. The filtrate was extracted with Et₂O (×2), pH was adjustedto ca. pH 14 by addition of NaOH pellets and extracted with Et₂O (×5).Combined extracts from the basic mixture were washed (brine), dried overNa₂SO₄, filtered and concentrated in vacuo, affording a second batch ofthe title compound, which was combined with the first batch. LC/MS(method D) 1.15 min, m/z 216 (M+H, ⁷⁹Br), 218 (M+H, ⁸¹Br).

Step 3: 1,1-Dimethylethyl{2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate

To a solution of {2-[(4-bromophenyl)oxy]ethyl}amine (1.89 g; 8.74 mmol;step 2 above), 4,4-dimethylcyclohexanone (1.10 g; 8.74 mmol; ExampleIII-1 Step 1) and HOAc (0.50 mL) in MeOH (50 mL) at rt was added NaBH₃CN(0.549 g; 8.74 mmol) in one portion and the mixture was stirred at roomtemperature. Upon consumption of {2-[(4-bromophenyl)oxy]ethyl}amine(Note 1), volatiles were removed in vacuo and the residue waspartitioned between 1M NaOH/CH₂Cl₂. Layers were separated and theaqueous layer was extracted with CH₂Cl₂ (×2). Combined organics werewashed (H₂O, brine), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was dissolved in CH₂Cl₂ (40 mL) along with Et₃N (1.22mL; 8.74 mmol), and a solution of (Boc)₂O (1.91 g; 8.74 mmol) in CH₂Cl₂(10 mL) was added. After 13 h the mixture was diluted with CH₂Cl₂,washed (H₂O, brine), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography (EtOAc/hexanes),affording the title compound as a colorless, waxy solid. LC/MS (methodA) 3.42 min, m/z 426, 428 (M+H, Br isotopes, 11-12%), 326, 328([M−Boc]+H, Br isotopes, 96-100%).

-   Note 1 Reaction progress was monitored by LC/MS; HOAc (˜1 equiv),    and small portions of NaBH₃CN (0.1-0.25 equiv) and    4,4-dimethylcyclohexanone (0.05 equiv) were added as necessary to    effect consumption of the amine.

The following examples were prepared from the appropriate amines and4,4-dimethylcyclohexanone (III-1 Step 1) according to the proceduredescribed in Example V-8 Step 3, with any significant deviations notedbelow table.

TABLE G Compounds of Formula V via reductive alkylation of thecorresponding amine and ketone Ex Structure/Name Characterization DataComments V-9 

LC/MS (method B) t_(R) 1.93 min; m/z 310, 312 (M + H, Br isotopes) Note1 V-10

LC/MS (method B) t_(R) 1.91 min; m/z 310, 312 (M + H, Br isotopes) Note1 V-11

LC/MS (method A) t_(R) 3.36 min, m/z 396, 398 (M + H, Br isotopes, 18-20%), 340, 342 ([M - C₄H₈] + H, Br isotopes, 94- 100%)4-Bromobenzylamine hydrochloride used HOAc omitted from reductiveamination. V-12

LC/MS (method A) t_(R) 3.44 min, m/z 410, 412 (M + H, Br isotopes, 6%),354 (79Br, 93%), 356 ([M - C4H8] + H, Br isotopes, 93-100%). V-13

Note 2 Note 2 Note 1 N-Boc carbamate formation was not observed within 6h under example conditions. The reaction was worked up per example V-8Step 3, and the title compound was purified by flash chromatography(EtOAc/hexanes). Note 2 2-Aminoindane hydrochloride and4-bromobenzaldehyde were used. The amine hydrochloride was admixed withan eqimolar amount of Et₃N in 1:1 THF/MeOH before addition to thealdehyde. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.32 (s, 9 H), 2.87-3.03 (m, 4H), 4.41 (br. s., 2 H), 4.71 (br. s., 1 H), 6.99-7.26 (m, 4 H),7.44-7.61 (m, 2 H).

Example V-14 1,1-dimethylethyl[2-(3-bromophenyl)ethyl]carbamate

To a solution of 2-bromophenethyl amine (2.0 g, 0.01 mol) inacetonitrile at room temperature was added di-tert-butyl dicarbonate(2.1 g, 0.01 mol) in one portion. After stirring at room temperature for72 hr the reaction mixture was concentrated in vacuo and the residue wasdissolved in ethyl acetate. The solution was washed with brine, dried(Na₂SO₄), filtered and concentrated in vacuo to give1,1-dimethylethyl[2-(3-bromophenyl)ethyl]carbamate as a yellow oil.LC/MS (method A) t_(R) 2.73 min; m/z 300 (M+H).

Example V-15 1,1-Dimethylethyl{2-[(4-bromo-3-methylphenyl)oxy]ethyl}carbamate

To a solution of 4-bromo-3-methylphenol (0.187 g; 1.00 mmol), N-Bocaminoethanol (0.39 mL; 2.5 mmol) and PPh₃ (0.655 g; 2.5 mmol) in anhydPhH (5 mL) at 0° C. was added DIAD (0.49 mL; 2.5 mmol), dropwise over 15min. The mixture was stirred 16 h at room temperature, diluted withEt₂O, washed (2×satd Na₂CO₃, 2×H₂O, brine), dried over Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/hexanes), affording the title compound as acolorless gum, which solidified on standing. LC/MS (method A) t_(R) 2.95min, m/z 330, 332 (M+H, Br isotopes, 2%), 352, 354 (M+Na, Br isotopes,40-43%), 230, 232 ([M−Boc]+H, Br isotopes, 100%).

Example V-16 1,1-Dimethylethyl6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

Step 1: 1,2,3,4-Tetrahydro-6-isoquinolinol hydrobromide

The title compound was synthesized in two steps fromm-methoxyphenethylamine, according to the procedure of Sall, D. J.;Grunewald, G. L. J. Med. Chem. 1987, 30, 2208 with the exception thatmethyl chloroformate was replaced with ethyl chloroformate in theBischler-Naperalski cyclization of 3-methoxyphenethylamine tointermediate 6-(methyloxy)-3,4-dihydro-1(2H)-isoquinolinone. ¹H NMR (400MHz, DMSO-d₆) δ 2.90 (t, J=6.2 Hz, 2H), 3.32 (m, 2H), 4.13 (t, J=4.6 Hz,2H), 6.59 (d, J=2.2 Hz, 1H), 6.65 (dd, J=8.4, 2.3 Hz, 1H), 7.00 (d,J=8.3 Hz, 1H), 9.00 (br. s, 2H).

Step 2: 1,1-Dimethylethyl6-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate

To a slurry of 1,2,3,4-tetrahydro-6-isoquinolinol hydrobromide (1.29 g;5.63 mmol; step 1 above) and Et₃N (3.13 mL; 22.5 mmol) in CH₂Cl₂ (30 mL)and THF (5 mL) at rt was added a solution of (Boc)₂O (2.46 g; 11.3 mmol)in THF (20 mL). The mixture was stirred 72 h at rt and concentrated invacuo. The residue was dissolved in CH₂Cl₂ and washed with H₂O. Theaqueous wash was back-extracted with CH₂Cl₂ (×2), Combined organics werewashed (H₂O, brine), dried over Na₂SO₄, filtered and concentrated invacuo. The residue was dissolved in CH₂Cl₂ (30 mL), piperidine (30 mL)was added, the mixture was stirred overnight at rt and concentrated invacuo. The residue was dissolved in EtOAc, washed (3×H₂O, brine), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue wasre-dissolved in EtOAc, washed (2×1M KHSO₄, H₂O, brine), dried overNa₂SO₄, filtered and concentrated in vacuo. The residue was purified byflash chromatography (EtOAc/hexanes), affording the title compound as acolorless gum. ¹H NMR (400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.76 (t, J=5.9Hz, 2H), 3.61 (br. t, J=5.8 Hz, 2H), 4.49 (s, 2H), 5.58 (br. s, 1H),6.63 (unresolved d, 1H), 6.68 (br. d, J=8.4 Hz, 1H), 6.95 (d, J=8.2 Hz,1H).

Step 3: 1,1-dimethylethyl6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

To a solution of 1,1-dimethylethyl6-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate (0.146 g; 0.586mmol) and Et₃N (0.17 mL; 1.2 mmol) in CH₂Cl₂ (5 mL) at 0° C. was addedTf₂O (0.11 mL; 0.67 mmol (dropwise over 2 min. The mixture was stirredovernight, gradually warming to room temperature, diluted with CH₂Cl₂,washed (water, brine), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography (EtOAc/hexanes), affordingthe title compound as a colorless gum which slowly solidified. ¹H NMR(400 MHz, CDCl₃) δ 1.49 (s, 9H), 2.87 (t, J=5.7 Hz, 2H), 3.66 (br. t,J=5.5 Hz, 2H), 4.59 (s, 2H), 7.04-7.12 (m, 2H), 7.18 (d, J=8.4 Hz, 1H).

Example V-17 (u23368-24-1) 1,1-Dimethylethyl7-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate

The title compound was obtained from 4-methoxyphenethylamine accordingto the procedure described for Example V-16, with the exceptions thatduring N-protection with (Boc)₂O (step 2): example V-17 used 1:1 EtOH/1MNaOH as solvent; Et₃N was omitted; after stirring 1 h at roomtemperature, the reaction was concentrated in vacuo, the residue wasacidified with 2M KHSO₄, extracted with EtOAc, dried and concentrated invacuo affording the intermediate 1,1-dimethylethyl7-hydroxy-3,4-dihydro-2(1H)-isoquinolinecarboxylate directly as a tansolid. 7-Hydroxy-intermediate (u22816-72-3): ¹H NMR (400 MHz, CDCl₃) δ1.42 (s, 9H), 2.63 (unresolved t, 2H), 3.49 (unresolved t, 2H), 4.38(br. s, 2H), 6.51 (br. s, 1H), 6.57 (br. d, J=7.9 Hz, 1H), 6.93 (d,J=7.9 Hz, 1H), 9.21 (br. s, 1H). 7-Triflate (title compound): ¹H NMR(400 MHz, CDCl₃) δ 1.50 (s, 9H), 2.85 (t, J=5.5 Hz, 2H), 3.66 (t, J=5.4Hz, 2H), 4.59 (s, 2H), 7.03 (unresolved d, 1H), 7.07 (partially resolveddd, J_(ortho)=8.5 Hz, 1H), 7.21 (d, J=8.4 Hz, 1H).

Example V-18 1,1-Dimethylethyl(4,4-dimethylcyclohexyl)(2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]oxy}ethyl)carbamate

A mixture of {2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate (0.529 g; 1.24 mmol; Example V-8 above),bis(pinacolato)diboron (0.439 g; 1.86 mmol), KOAc (0.365 g; 3.72 mmol),and PdCl₂(dppf).CH₂Cl₂ (0.030 g; 0.037 mmol) in anhyd DMSO (5 mL) wassparged with N₂ for 5 min, then heated to 80° C. under N₂. After 16.5 hthe mixture was cooled, poured into H₂O and extracted with EtOAc (×3).Combined organics were washed (H₂O, brine), dried over Na₂SO₄, adsorbedonto a small amount of silica gel and purified by flash chromatography(EtOAc/hexanes), affording the title compound as a colorless gum. LC/MSmethod A) t_(R) 3.50 min, m/z 474 (M+H, 26%), 374 ([M−Boc]+H, 100%).

Example V-19 1,1-dimethylethyl(4,4-dimethylcyclohexyl){[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate

The title compound was synthesized from1,1-dimethylethyl[(4-bromophenyl)methyl](4,4-dimethylcyclohexyl)carbamate (Example V-11) according to the procedure described in ExampleV-18. LC/MS (method A) t_(R) 3.48 min, m/z 444 (M+H, 19%), 466 (M+Na,100%).

Example V-20 1,1-dimethylethyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2(1H)-isoquinolinecarboxylate

The title compound was prepared from 1,1-dimethylethyl6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate(Example V-16) according to the procedure described in Example V-18. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.28 (s, 12H), 1.42 (s, 9H), 2.78 (t, J=6.1Hz, 2H), 3.54 (t, J=6.0 Hz, 2H), 4.50 (br. s., 2H), 7.16 (d, J=7.8 Hz,1H), 7.45 (d, J=1.4 Hz, 2H).

Example V-215-bromo-N-(4,4-dimethylcyclohexyl)-2,3-dihydro-1H-inden-1-amine

To a slurry of 5-bromo-1-indanone (0.449 g; 2.13 mmol) and4,4-dimethylcyclohexanamine (2.24 mmol; Note 1) under N₂ was addedTi(OiPr)₄ (0.94 mL; 3.2 mmol) via syringe. The mixture was stirred 16 hat room temperature, a solution of NaBH₃CN (0.134 g; 2.13 mmol) in EtOH(5 mL) was added and stirring continued an additional 4 h. Water wasadded and the whole was filtered through a pad of Celite (washed 2×EtOH,2×THF). Combine filtrate and washings were concentrated in vacuo, theresidue was taken up in CH₂Cl₂ and stirred under 1N NaOH for 1 h. Layerswere separated, the aqueous layer was extracted with CH₂Cl₂ (×2),combined organics were washed (water, brine), dried over Na₂SO₄ andconcentrated in vacuo. The residue was dissolved in MeOH/THF/HOAc(15/3/0.3 mL respectively), NaBH₃CN (0.134 g; 2.13 mmol) was added andthe mixture was stirred at room temperature overnight. After 17 h themixture was concentrated in vacuo, partitioned between CH₂Cl₂/1N NaOHand the layers were separated. The aqueous layer was extracted withCH₂Cl₂ (×2), combined organics were washed (water, brine), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/hexanes; Note 2), affording the title compound asa pale yellow syrup. LC/MS (method A) t_(R) 1.79 min; m/z 322, 324 (M+H,Br isotopes).

-   Note 1: 4,4-dimethylcyclohexanamine was obtained from an equimolar    amount of the hydrochloride salt (Example III-1 Step 1) by    partitioning between satd Na₂CO₃/Et₂O, drying the organic layer over    Na₂SO₄, and concentrating in vacuo before use.-   Note 2: Amine-functionalized silica gel (Teledyne Isco catalog    #68-2203-102) was used for purification.

Example V-22{4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3,5-difluorophenyl}boronicacid

A mixture of 2,3-dihydro-1H-inden-2-amine (0.780 mL, 5.99 mmol),(3,5-difluoro-4-formylphenyl)boronic acid (1.0 g, 5.99 mmol) and aceticacid (0.710 mL, 12.0 mmol) in THF (12 mL) was stirred at roomtemperature for 1 hr. To the solution was added NaBH(OAc)₃ (3.81 g, 18.0mmol) and the mixture stirred at room temperature for 16 hr. The mixturewas diluted with EtOAc then washed with satd Na₂CO₃. The combined layerswere filtered and the filter cake washed with H₂O and EtOAc to give{4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3,5-difluorophenyl}boronicacid as a beige glass. LC/MS (method A) t_(R) 0.48 min; m/z 304 (M+H).

Compounds of Formula VI

Example VI-1 1,1-dimethylethyl(2-{[4′-(acetylamino)-4-biphenylyl]oxy}ethyl)(4,4-dimethylcyclohexyl)carbamate

A mixture of 1,1-dimethylethyl{2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate (0.085 g;0.20 mmol; Example V-8), [4-(acetylamino)phenyl]boronic acid (0.040 g;0.22 mmol), PdCl₂(dppf).CH₂Cl₂ (0.005 g; 0.006 mmol), Na₂CO₃ (2 mL of a2M solution) and DME (2 mL) was sparged with N₂ for 10 minutes at roomtemperature and heated at 80° for 1 h (until consumption of the arylbromide, as judged by LC/MS). Upon cooling, the mixture was partitionedbetween EtOAc/H₂O, layers were separated and the aqueous layer wasextracted with EtOAc (×2). Combined organics were washed (brine), driedover Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (EtOAc/hexanes), affording the titlecompound as a pale yellow solid. LC/MS (method A) t_(R) 3.29 min, m/z481 (M+H, 53%), 381 ([M−Boc]+H, 100%).

The following examples were prepared from the appropriate arylhalide/triflate and aryl boronic acid/ester according to the proceduredescribed for Example VI-1, with any significant deviation noted belowtable.

TABLE H Compounds of Formula VI from Suzuki coupling of Compounds ofFormula IV or V. Ex Structure/Name Characterization Data Comments VI-2

LC/MS (method A) t_(R) 3.31 min, m/z 481 (M + H, 28%), 381 ([M - Boc] +H, 100%) Aryl bromide V-8 and 3-(acetylamino phenylboronic acid usedVI-3

LC/MS (method A) t_(R) 3.26 min, m/z 515 (M - H). Aryl bromide V-8 and3-[(methylsulfonyl) amino]-phenylboronic acid used VI-4

LC/MS (method A) t_(R) 2.60 min, m/z 488 (M - H). Aryl bromide IV-21 andaryl boronate V-18 used. VI-5

LC/MS (method A) 2.55 min; m/z 490 (M + H). Aryl bromide IV-22 and arylboronate V-18 used. Pd(PPh3)4 used as catalyst VI-6

LC/MS (method A) t_(R) 3.23 min; m/z 481 (M + H, 24%), 503 (M + Na,100%).. Aryl bromide IV-1 and aryl boronate V-18 used. VI-7

LC/MS (method A) t_(R) 3.27 min; m/z 481 (M + H, 5%), 503 (M + Na,100%).. Aryl bromide IV-2 and aryl boronate V-18 used. VI-8

Note 1 Used aryl bromide V- 11 and 3-(aminocarbonyl) phenylboronic acid.VI-9

LC/MS (method A) t_(R) 3.09 min; m/z 437 (M + H, 81%), 381 ([M - C₄H₈] +H, 100%) Used aryl bromide V- 11 and 4-(aminocarbonyl) phenylboronicacid.  VI-10

LC/MS (method A) t_(R) 3.21 min; m/z 451 (M + H, 12%), 395 ([M - C₄H₈] +H, 100%) Used aryl bromide IV- 1 and aryl boronate V- 19.  VI-11

LC/MS (method A) t_(R) 3.21 min; m/z 451 (M + H, 25%), 473 (M + Na,100%), 395 ([M - C₄H₈] + H, 66%) Used aryl bromide IV- 2 and arylboronate V-19.  VI-12

LC/MS (method A) t_(R) 3.19 min, m/z 451 (M + H, 24%), 901 (2M + H,100%), 351 ([M - Boc] + H, 30%) Used aryl bromide V- 12 and 3-aminocarbonyl phenylboronic acid  VI-13

LC/MS (meihod E) t_(R) 1.13 min, m/z 450 ([M - C₄H₈] + H, 100%), 406([M - Boc] + H, 55%) Used aryl bromide IV- 35 and aryl boronate V-18. VI-14

LC/MS (method E) t_(R) 1.12 min, m/z 544 (M + H, 10%), 488 ([M - C₄H₈] +H, 100%) Used aryl bromide IV- 40 and aryl boronate V-18. Note 1 ¹H NMR(400 MHz, CDCl₃) δ 0.86 (s, 3H), 0.88 (s, 3H), 1.13-1.74 (m, 17 H),3.42-4.10 (m, 1H), 4.35-4.54 (m, 2H), 5.74 (br. s, 1H), 6.19 (br. s,1H), 7.30-7.36 (m, 2H), 7.51 (app. t, J = 7.7 Hz, 1H), 7.56 (m, 2H),7.75 (m, 2H), 8.06 (br. s, 1H).

Example VI-15 1,1-Dimethylethyl(4,4-dimethylcyclohexyl)(2-{[3′-(1,2,4-oxadiazol-3-yl)-4-biphenylyl]oxy}ethyl)carbamate

Step 1: 1,1-dimethylethyl{2-[(3′-cyano-4-biphenylyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate

A mixture of m-cyanophenyl boronic acid (0.086 g; 0.59 mmol),1,1-dimethylethyl{2-[(4-bromophenyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate (0.250 g;0.59 mmol; Example V-8), PdCl₂(dppf).CH₂Cl₂, 2M Na₂CO₃ (4 mL) and DME (4mL) was sparged 5 min with N₂ and then heated to 80° C. for 5 h. Uponcooling, the mixture was diluted with EtOAc, washed with water and thewashing was back-extracted with EtOAc (×2). Combined organics werewashed (water, brine), dried over Na₂SO₄, adsorbed onto a minimal amountof silica gel and purified by flash chromatography (EtOAc/hexanes),affording the title compound as a colorless gum. ¹H NMR (400 MHz, CDCl₃)δ 0.92 (s, 3H), 0.94 (s, 3H, partially overlapping 0.92), 1.21-1.87 (m,17H), 3.45-3.63 (m, 2H), 3.88 (br. s, 1H), 4.10 (br. s, 2H), 7.00 (m,2H), 7.49 (m, 2H), 7.52 (d, J=7.8 Hz, 1H; partially overlapping 7.49),7.58 (d, J=7.6 Hz, 1H), 7.77 (partially resolved ddd, J_(ortho)=7.8 Hz,1H), 7.82 (unresolved dd, 1H).

Step 2:1,1-Dimethylethyl(4,4-dimethylcyclohexyl)(2-{[3′-(1,2,4-oxadiazol-3-yl)-4-biphenylyl]oxy}ethyl)carbamate

To a solution of 1,1-dimethylethyl{2-[(3′-cyano-4-biphenylyl)oxy]ethyl}(4,4-dimethylcyclohexyl)carbamate(0.125 g; 0.279 mmol; step 1 above) in EtOH (2.5 mL) at room temperaturewas added a solution of hydroxylamine (0.25 mL of a 50 wt % aqsolution). The mixture was stirred 70 h at room temperature andvolatiles were removed in vacuo (1×PhMe chase). The residue wasdissolved in trimethyl orthoformate (2 mL), TsOH.H₂O (0.0025 g; 0.013mmol) was added and the mixture was heated at 100° C. in a sealed vialfor 1 h. Upon cooling, the mixture was adsorbed onto a small amount ofsilica gel and purified by flash chromatography (EtOAc/hexanes),affording the title compound as a colorless gum. LC/MS (method A) t_(R)3.34 min, m/z 492 (M+H, 5%), 514 (M+Na, 100%), 392 ([M−Boc]+H, 53%).

Example VI-16 1,1-dimethylethyl(4,4-dimethylcyclohexyl)[(3-{[(2-phenylethyl)amino]carbonyl}-4-biphenylyl)methyl]carbamate

Step 1: methyl4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)methyl]-3-biphenylcarboxylate

A flask equipped with a septum-sealed reflux condenser was charged with1,1-dimethylethyl[(4-bromophenyl)methyl](4,4-dimethylcyclohexyl)carbamate(0.988 g; 2.49 mmol; Example V-11),{3-[(methyloxy)carbonyl]phenyl}boronic acid (0.493 g; 2.74 mmol),Pd(OAc)₂ (0.0028 g; 0.012 mmol) and2-(2′,6′-dimethoxybiphenyl)di-cyclohexylphosphine (S-Phos; 0.010 g;0.025 mmol) was evacuated and back-filled with N₂ several times.PhMe/EtOH (4:1 v/v, 7.5 mL), and 2M Na₂CO₃ were added via syringethrough the condenser's septum and the mixture was heated under refluxfor 2 h (until consumption of the aryl bromide was observed). Uponcooling, the mixture was poured into EtOAc/water, the whole was filteredthrough a 0.45 μm PTFE membrane filter and the layers were separated.The aqueous layer was extracted with EtOAc, combined organics werewashed (brine), dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography (EtOAc/hexanes), affording thetitle compound as a colorless gum/syrup. ¹H NMR (400 MHz, DMSO-d₆) δ ppm0.85 (s, 6H), 1.07-1.79 (m, 18H), 3.89 (s, 3H), 4.42 (br. s., 2H), 7.36(d, J=8.03 Hz, 2H), 7.62 (t, J=7.85 Hz, 1H), 7.67 (d, J=8.03 Hz, 2H),7.95 (t, J=6.96 Hz, 2H), 8.18 (s, 1H).

Step 2:4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-methyl]-3-biphenylcarboxylicacid

A mixture of methyl4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}-amino)methyl]-3-biphenylcarboxylate(0.850 g; 1.88 mmol), LiOH.H₂O (0.395 g; 9.40 mmol), water (2 mL) andTHF (20 mL) was heated under reflux for 24 h, cooled and concentrated invacuo. The residue was partitioned between EtOAc/1N KHSO₄, layers wereseparated and the organic layer was extracted with EtOAc (×2). combinedorganics were washed (water, brine), dried over Na₂SO₄ and concentratedin vacuo affording the title compound as a colorless foam. LC/MS (methodE) t_(R) 0.77 min; m/z 464 (M−H).

Step 3: 1,1-dimethylethyl(4,4-dimethylcyclohexyl)[(3′-{[(2-phenylethyl)amino]-carbonyl}-4-biphenylyl)methyl]carbamate

To a solution of4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]carbonyl}amino)-methyl]-3-biphenylcarboxylicacid (0.100 g; 0.23 mmol) in DMF (2 mL) was added DIEA (0.035 mL; 0.25mmol), and HATU (0.095 g; 0.25 mmol). The solution was aged 5 min atroom temperature and phenethylamine (0.031 mL; 0.25 mmol) was added.After 45 min the mixture was partitioned between EtOAc and half-satdNa₂CO₃, layers were separated and the aqueous layer was extracted withEtOAc (×2). Combined organics were washed (water, brine), dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography (EtOAc/hexanes), affording the title compound as acolorless gum. LC/MS (method E) t_(R) 1.19 min; m/z 541 (M+H).

The following were prepared from4′-[((4,4-dimethylcyclohexyl){[(1,1-dimethylethyl)oxy]-carbonyl}amino)methyl]-3-biphenylcarboxylicacid (Example VI-16 Step 2) and the appropriate amines according to theprocedure described for Example VI-16 Step 3.

TABLE I Compounds of Formula VI from amide coupling to Example VI-16Step 2 Ex Structure/Name Characterization Data Comments VI-17

LC/MS (method E) t_(R) 1.22 min; m/z 555 (M + H). VI-18

LC/MS (method E) t_(R) 1.17 min; m/z 527 (M + H). VI-19

LC/MS (method E) t_(R) 1.27 min; m/z 617 (M + H)

Example VI-20 1,1-dimethylethyl2,3-dihydro-1H-inden-2-yl{[3′-(1H-imidazol-4-yl)-4-biphenylyl]methyl}carbamate

Step 1: 1,1-dimethylethyl2,3-dihydro-1H-inden-2-yl[(3′-formyl-4-biphenylyl)-methyl]carbamate

The title compound was prepared from1,1-dimethylethyl[(4-bromophenyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate(Example V-13) and 3-formylphenylboronic acid according to the proceduredescribed in Example VI-16 Step 1. 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.35(s, 9H), 3.00 (d, J=8.56 Hz, 4H), 4.51 (br. s., 2H), 7.06-7.19 (m, 4H),7.34 (d, J=8.03 Hz, 2H), 7.69 (t, J=7.67 Hz, 1H), 7.72-7.77 (m, 2H),7.86-7.91 (m, 1H), 8.01-8.06 (m, 1H), 8.19-8.24 (m, 1H), 10.10 (s, 1H).

Step 2: 1,1-dimethylethyl2,3-dihydro-1H-inden-2-yl[(3′-{4-[(4-methylphenyl)-sulfonyl]-4,5-dihydro-1,3-oxazol-5-yl}-4-biphenylyl)methyl]carbamate

To a solution of 1,1-dimethylethyl2,3-dihydro-1H-inden-2-yl[(3′-formyl-4-biphenylyl)-methyl]carbamate(0.188 g; 0.44 mmol) and TosMIC (0.086 g; 0.44 mmol) in EtOH at roomtemperature was added NaCN (0.002 g; 0.04 mmol). The mixture was stirred30 min, diluted with water and extracted with EtOAc (×3). combinedorganics were washed (water, brine), dried over Na₂SO₄ and concentratedin vacuo affording the title compound as a colorless gum, used withoutfurther purification. 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s, 9H), 2.41(s, 3H), 2.99 (d, J=8.38 Hz, 4H), 4.50 (br. s., 2H), 5.65 (dd, J=5.98,1.69 Hz, 1H), 5.96 (d, J=5.89 Hz, 1H), 7.07-7.18 (m, 5H), 7.25(partially resolved dd, J=7.85 Hz, 1H), 7.28-7.34 (m, 2H), 7.40(unresolved dd, 1H), 7.46-7.52 (m, 3H), 7.57-7.64 (m, 2H), 7.68 (dd,J=8.03, 1.25 Hz, 1H), 7.74 (d, J=1.25 Hz, 1H), 7.83-7.90 (m, 2H).

Step 3: 1,1-dimethylethyl2,3-dihydro-1H-inden-2-yl{[3′-(1H-imidazol-4-yl)-4-biphenylyl]methyl}carbamate

A mixture of 1,1-dimethylethyl2,3-dihydro-1H-inden-2-yl[(3′-{4-[(4-methylphenyl)-sulfonyl]-4,5-dihydro-1,3-oxazol-5-yl}-4-biphenyl)methyl]carbamate(0.260 g; 0.418 mmol) and NH₃ in MeOH (5 mL of a 7M solution) was sealedin a pressure tube and heated at 90° C. After 51 h, volatiles wereremoved in vacuo, a fresh charge of NH₃ in MeOH was added to the residueand heating was continued an additional 15 h. Upon cooling, the wholewas adsorbed onto a minimal amount of Celite and purified by flashchromatography (EtOAc/hexanes), affording the title compound as acolorless film. 1H NMR (400 MHz, CDCl₃) δ ppm 1.42 (s, 9H), 2.94-3.18(m, J=15.87, 15.79, 15.79, 8.20 Hz, 4H), 4.48 (br. s., 2H), 4.65-5.22(br. m, 1H), 7.13 (s, 6H), 7.24 (m, 2H), 7.36 (s, 1H), 7.39-7.51 (m,3H), 7.54-7.60 (m, 2H), 7.64-7.71 (m, 3H), 7.96 (br. s., 1H).

Compounds of Formula VII

Intermediates of Formula VII Intermediate I-VII-1: 1,1-Dimethylethyl(2-{[3′-(aminocarbonyl)-2-methyl-4-biphenylyl]oxy}ethyl)carbamate

A mixture of 1,1-dimethylethyl{2-[(4-bromo-3-methylphenyl)oxy]ethyl}carbamate (0.102 g, 0.31 mmol;Example V-15), 3-(aminocarbonyl)phenylboronic acid (0.056 g; 0.34 mmol),PdCl₂(dppf).CH₂Cl₂ (0.0075 g; 0.01 mmol), DME (2 mL) and 2M Na₂CO₃ (2mL) was degassed by sparging with N₂, (5-10 min) then stirred at 80° C.for 5.5 h. Upon cooling, the mixture was diluted with EtOAc washed(water, brine), dried over Na₂SO₄ and concentrated in vacuo. The residuewas purified by flash chromatography (EtOAc/hexanes), affording thetitle compound as a colorless foam. LC/MS (method A) 2.59 min, m/z 371(M+1, 2%), 392 (M+Na, 53%), 271 ([M−Boc]+H, 100%).

The following intermediates were prepared from the appropriate arylhalide/triflate and aryl boronic acid/boronate according to theprocedure described for I-VII-1, with any significant deviations notedbelow table.

TABLE J Intermediates to Compounds of Formula VII Ex Structure/NameCharacterization Data Comments I-VII-2

Note 5 Used aryl bromide V- 14 and 4- (aminocarbonyl) phenylboronicacid. Note 1, 2 I-VII-3

Note 6 Used 4(aminocarbonyl) phenyl boronic acid and the correspondingaryl halide. Note 1, 2 I-VII-4

Note 7 Used product of Ex III-12 Step 1 as aryl bromide and3-(aminocarbonyl) phenyl boronic acid. Note 3 I-VII-5

LC/MS (method A) 2.61 min; m/z 367 (M + H) Used aryl bromide IV-2 andaryl boronate V-20. Note 3 I-VII-6

LC/MS (method A) 2.6 min; m/z 371 (M + H, 5%), 315 ([M - C4H8] + H,100%), 271 ([M - Boc] + H, 70%) Used aryl bromide IV-16 and arylboronate V-20. Note 3 I-VII-7

LC/MS (method A) 2.02 min; m/z 376 (M + H) Used aryl bromide IV-21 andaryl boronate 20. Note 3 I-VII-8

LC/MS (method E) 0.73 min; m/z 341 (M + H) Used aryl bromide V- 14 and3-(aminocarbonyl)- phenyl boronic acid Note 2, 3, 4. Note 1 1:1Acetonitrile/0.4M Na₂CO₃ was used instead of DME/2M Na₂CO₃. Pd(PPh₃)₄was used instead of PdCl₂(dppf).CH₂Cl₂. Note 2 Chromatographicpurification omitted. Note 3 4:1 PhMe/EtOH used instead of DME. Note 42-(2′,6′-dimethoxybiphenyl)di-cyclohexylphosphine (S-Phos)/Pd(OAc)₂ wasused instead of PdCl₂(dppf).CH₂Cl₂. Note 5 (I-VII-2) ¹H NMR (400 MHz,DMSO-d6) delta ppm 1.33 (s, 9 H); 2.75 (t, J = 7.3 Hz, 2 H); 3.19 (m, 2H); 6.91 (t, J = 5.5 Hz, 1 H); 7.20 (d, J = 7.51, 1 H), 7.38 (m, 2H),7.53 (m, 2H), 7.72 (d, J = 8.2, 2H), 7.92 (d, J = 8.4, 2H), 8.01 (br. s,1H). Note 6 (I-V11-3) ¹H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (s, 9H),1.50-1.61 (qd, 2H), 1.78 (br. d, 2H), 2.71-2.77 (br. m, 3H), 4.01-4.09(br. d, 2H), 7.25 (d, 1H), 7.36-7.40 (m, 2H), 7.52-7.56 (m, 2H), 7.73(d, 2H), 7.93 (d, 2H), 8.00 (s, 1H). Note 7 (I-V11-4) ¹H NMR (400 MHz,DMSO-d6) δ ppm 1.40 (s, 9 H), 2.82 (td, J = 15.1, 7.0 Hz, 2 H), 3.16(td, J = 14.3, 7.7 Hz, 2 H), 4.26 (app. sext, J = 7.0 Hz, 1 H), 7.21 (d,J = 6.6 Hz, 1 H), 7.29 (d, J = 7.7 Hz, 1 H), 7.43 (br. s., 1 H),7.46-7.54 (m, 2 H), 7.55 (s, 2 H), 7.77 (d, J = 8.0 Hz, 1 H), 7.82 (d, J= 7.7 Hz, 1 H), 8.07-8.15 (m, 2 H).

Intermediate I-VII-9: 1,1-dimethylethyl6-[3-(aminocarbonyl)phenyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

A solution of 3-(aminocarbonyl)phenyl boronic acid (0.663 g; 4.0 mmol),1,1-dimethylethyl6-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate (1.28 g; 3.35 mmol; Ex V-16) in DMF (10 mL) was sparged withN₂ for 10 min, K₃PO₄ (1.7 g; 8.0 mmol) and Pd(PPh₃)₄ (0.193 g; 0.17mmol) were added and the mixture was stirred at 100° C. for 2 h. Uponcooling, the mixture was poured into water and extracted with EtOAc(×3). Combined organics were washed (H₂O, brine), and dried over Na₂SO₄.Residual solids were collected from the aqueous layer by filtration,air-dried, dissolved in hot EtOH and combined with the dried EtOAcextracts. The whole was adsorbed onto a minimal amount of silica gel andpurified by flash chromatography (EtOAc/hexanes), affording the titlecompound as a as a colorless solid. LC/MS (method B) 2.69 min; m/z 297([M−C₄H₈]+H, 70%), 253 ([M−Boc]+H, 74%).

Intermediate I-VII-10: 1,1-dimethylethyl7-[4-(amino-carbonyl)phenyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate

The title compound was prepared from 1,1-dimethylethyl7-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2(1H)-isoquinolinecarboxylate (Ex V-17) and 4-(aminocarbonyl)-phenyl boronic acidaccording to the procedure described for I-VII-9. Tan solid; LC/MS(method A) 2.62 min; m/z 353 (M+H, 75%), 297 ([M−C₄H₈]+H, 100%).

-   Note Intermediates I-VII-9 and I-VII-10 may also be prepared using    conventional biphasic conditions similar to I-VII-1, however, in our    hands, the anhydrous conditions described above proved higher    yielding for tetrahydroisoquinoline (THiQ) triflates.

Compounds of Formula VII Example VII-14′-[(2-Aminoethyl)oxy]-2′-methyl-3-biphenylcarboxamide trifluoroacetate

To a solution of 1,1-dimethylethyl(2-{[3′-(aminocarbonyl)-2-methyl-4-biphenylyl]oxy}ethyl)carbamate (0.090g; 0.24 mmol; I-VII-2) and Et₃SiH (0.1 mL; 0.6 mmol) in CH₂Cl₂ (5 mL) atroom temperature was added TFA (1 mL) in one portion. The mixture wasaged 2 h and concentrated in vacuo, affording the title compound as apale yellow gum which was used without further purification. LC/MS(method A) 1.18 min, m/z 271 (M+H).

Example VII-2 3′-(2-aminoethyl)-4-biphenylcarboxamide

To a solution of 1,1-dimethylethyl{2-[4′-(aminocarbonyl)-3-biphenylyl]ethyl}-carbamate (1.81 g, 0.005 mol)in CH₂Cl₂ (50 mL) at room temperature was added trifluoroacetic acid (15mL) in one portion. After 1 hr the mixture was cooled in an ice bath and1M K₂CO₃ (200 mL) and chloroform were added. The aqueous phase wasextracted several times with mixtures of ethyl acetate, dichloromethaneand chloroform. Residual solids were collected by filtration, affordingthe title compound as a white solid; LC/MS (method A) 1.04 min; m/z 241(M+H). Combined organic extracts were dried over Na₂SO₄ and concentratedin vacuo affording an additional batch of the title compound (combinedwith the solid collected above). This product was used without furtherpurification.

Example VII-3 3′-(4-piperidinyl)-4-biphenylcarboxamide hydrochloride

A mixture of 1,1-dimethylethyl4-[4′-(aminocarbonyl)-3-biphenylyl]-1-piperidine carboxylate (0.95 g,0.0025 mol; I-VII-3) and 4N HCl in dioxane (5 mL) in dichloromethane (5mL) was stirred at ambient temperature for 3 hr. The resulting solid wascollected by filtration, washed with dichloromethane, diethyl ether andair-dried to give the title compound as a white solid, used withoutfurther purification. LC/MS (method A) 1.17 min; m/z 281 (M+H).

Example VII-4 3-(1,2,3,4-tetrahydro-6-isoquinolinyl)benzamide

To a solution of 1,1-dimethylethyl6-[3-(aminocarbonyl)phenyl]-3,4-dihydro-2(1H)-isoquinolinecarboxylate(0.725 g; 2.20 mmol; I-VII-9) and Et₃SiH (0.88 mL; 5.5 mmol) in CH₂Cl₂(25 mL) at room temperature was added TFA (10 mL) in one portion. Themixture was aged 3 h and concentrated in vacuo (2×PhMe chase). Theresidue was partitioned between satd Na₂CO₃/CHCl₃ (Note 1), layers wereseparated and the aqueous layer was extracted with CHCl₃ (×4). Combinedorganics were washed (water, brine), dried over Na₂SO₄ and concentratedin vacuo, affording the title compound as a colorless solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 2.76 (t, J=5.7 Hz, 2H), 2.96 (t, J=5.8 Hz, 2H), 3.87(s, 2H), 7.11 (d, J=7.9 Hz, 1H), 7.40-7.48 (m, 3H), 7.51 (t, J=7.8 Hz,1H), 7.78 (ddd, J=7.7, 1.8, 1.1 Hz, 1H), 7.82 (ddd, J=7.8, 1.4, 1.3 Hz,1H), 8.10 (s, 1H), 8.12 (t, J=1.6 Hz, 1H).

-   Note 1 A small amount of MeOH was added during extraction with CHCl₃    to facilitate dissolution of the solid residue.

Example VII-5 3-(2-amino-2,3-dihydro-1H-inden-5-yl)benzamide

The title compound was prepared from 1,1-dimethylethyl{5-[3-(amino-carbonyl)phenyl]-2,3-dihydro-1H-inden-2-yl}carbamate(I-VII-4) according to the procedure described in Example VII-4. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.71 (br. s., 2H), 2.55-2.69 (m, 2H), 3.00-3.14(m, 2H), 3.68-3.77 (m, 1H), 7.28 (d, J=7.7 Hz, 1H), 7.42 (s, 1H), 7.46(dd, J=7.7, 1.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 7.54 (s, 1H), 7.77(app. ddd, J=7.8, 1.8, 1.1 Hz, 1H), 7.82 (app. ddd, J=7.8, 1.7, 1.2 Hz,1H), 8.10 (br. s., 1H), 8.12 (t, J=1.7 Hz, 1H).

Example VII-6 3′-(2-aminoethyl)-3-biphenylcarboxamide

The title compound was prepared from 1,1-dimethylethyl{2-[3′-(aminocarbonyl)-3-biphenylyl]ethyl}carbamate (I-VII-8) accordingto the procedure described in Example VII-4. ¹H NMR (400 MHz, DMSO-d₆) δppm 1.43 (br. s., 2H), 2.68-2.75 (m, 2H), 2.79-2.85 (m, 2H), 7.23 (d,J=7.7 Hz, 1H), 7.39 (app. t, J=7.8 Hz, 1H), 7.44 (br. s., 1H), 7.50-7.56(m, 3H), 7.81 (app. ddd, J=7.8, 1.8, 1.2 Hz, 1H), 7.85 (app. ddd, J=7.7,1.6, 1.1 Hz, 1H), 8.11 (br. s., 1H), 8.14 (app. t, J=1.6 Hz, 1H).

Example VII-7 4′-(2-aminoethyl)-3-biphenylcarboxamide

The title compound was prepared from 3-(aminocarbonyl)-phenyl boronicacid and 4-bromophenethylamine. according to the procedure described forintermediate I-VII-1 with the exceptions that 4:1 PhMe/EtOH was sued asorganic solvent (instead of DME) and the chromatographic purificationstep was omitted. LC/MS (method E) 0.53 min; m/z 241 (M+H).

Compounds of Formula IX

Formula IX Intermediates

The following compounds were employed as precursors of Formula IXcompounds, and at the time of this writing were not readily availablefrom commercial suppliers.

Intermediate I-IX-1: 4-bromo-3-methylbenzaldehyde

To a solution of 4-bromo-3-methylbenzonitrile (0.975 g; 5.00 mmol) inanhyd CH₂Cl₂ (7.5 mL) at −40° C. was added DIBAL-H (7.5 mL of a 1Msolution in hexanes; 7.5 mmol), dropwise over 5 min. The mixture wasstirred 30 min at −40° C., removed from the cooling bath and stirred 1 hat rt. The mixture was cooled in an ice bath, and excess hydride wasquenched by dropwise addition of MeOH. After stirring 20 min, Rochelle'ssalt (satd aq. solution) was added, the mixture was stirred at rtovernight, and the layers were separated. The aqueous layer wasextracted with CH₂Cl₂ (×2), combined organics were washed (H₂O, brine),dried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash chromatography (EtOAc/hexanes), affording the titlecompound as a colorless solid (Note 1). ¹H NMR (400 MHz, CDCl₃) δ 2.49(s, 1H), 7.56 (dd, J=8.2 Hz, 1.8 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.74(d, J=1.7 Hz, 1H, partially overlapping 7.72), 9.96 (s, 1H).

-   Note 1 The title compound was oxidized rapidly on standing in air to    a mixture of benzaldehyde and benzoic acid.

Intermediate I-IX-2: 4-bromo-2-methylbenzaldehyde

The title compound was prepared from 4-bromo-2-methylbenzonitrileaccording to the procedure described for Example I-IX-1 with exceptionsas follows: the reaction temperature was −78° C. (instead of −40° C.);the reaction was quenched with MeOH at −78° C. (instead of ice bathtemp), followed by addition of 6M HCl at −78° C. (instead of satdRochelle's salt); after quenching the reaction mixture was stirred 30min at room temperature (instead of overnight). Colorless oil; ¹H NMR(400 MHz, CDCl₃) δ 2.65 (s, 3H), 7.45 (br. s, 1H), 7.51 (dd, J=8.3, 1.7Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 10.22 (s, 1H).

Intermediate I-IX-3: 4-formyl-2-(methoxy)phenyltrifluoromethanesulfonate

To a solution of 4-hydroxy-3-(methoxy)benzaldehyde (0.760 g; 5.00 mmol)and Et₃N (1.39 mL; 10.0 mmol) in anhyd CH₂Cl₂ (10 mL) at 0° C. was addedTf₂O (0.92 mL; 5.5 mmol), dropwise over 2 min. The mixture was allowedto warm slowly to room temperature (overnight), diluted with CH₂Cl₂,washed (water, brine), dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash chromatography (EtOAc/hexanes), affordingthe title compound as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 4.01(s, 3H), 7.42 (d, J=8.2 Hz, 1H), 7.52 (dd, J=8.2, 1.8 Hz, 1H), 7.57 (d,J=1.7 Hz, 1H), 9.99 (s, 1H).

Intermediate I-IX-4 (I-17): 2-chloro-4-formylphenyltrifluoromethanesulfonate

The title compound was synthesized from 3-chloro-4-hydroxybenzaldehyde,as described for the synthesis of Example I-IX-3 above. ¹H NMR (400 MHz,CDCl₃) δ 7.56 (d, J=8.5 Hz, 1H), 7.89 (dd, J=8.5 Hz, 1.9 Hz, 1H), 8.07(d, J=1.9 Hz, 1H), 10.01 (s, 1H).

Intermediate I-IX-5 (I-18): 2-fluoro-4-formylphenyltrifluoromethanesulfonate

The title compound was synthesized from 3-fluoro-4-hydroxybenzaldehyde,as described for the synthesis of Example I-IX-3 above. ¹H NMR (400 MHz,CDCl₃) δ 7.56 (m, 1H), 7.80 (m, 2H), 10.01 (d, J=1.5 Hz, 1H).

Intermediate I-IX-6 (I-19): 4-iodo-3-(trifluoromethyl)benzonitrile

To a slurry of 4-amino-3-(trifluoromethyl)benzonitrile (5.48 g; 29.5mmol) in HBF₄ (50 mL; 48%) at −10° C. was added NaNO₂ (2.24 g; 32.4mmol), portionwise over 10 min. The mixture was stirred 30 min,precipitated solids were collected by filtration (Note 1) and (withoutdelay) added portionwise to a solution of KI (7.84 g; 47.2 mmol) inacetone/water (50 mL of a 40% v/v solution). The mixture was decolorizedby addition of 10 wt % Na₂S₂O₃, precipitate was collected by filtration,washed with water and slurried in PhMe. The slurry was concentrated todryness, affording the title compound as a pale orange solid, usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (dd,J=8.1, 1.6 Hz, 1H), 8.27 (d, J=1.5 Hz, 1H), 8.37 (d, J=8.1 Hz, 1H).

-   Note 1 Solid was not allowed to dry completely on the filter.

Intermediate I-IX-7: 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane

To a solution of 4-iodo-2-(trifluoromethyl)benzonitrile (1.89 g; 6.38mmol, Note 1) in CH₂Cl₂ (15 mL) at −40° C. was added DIBAL-H (9.6 mL ofa 1.0M solution in CH₂Cl₂; 9.6 mmol), dropwise over 5 min. The mixturewas stirred 30 min, quenched by dropwise addition of MeOH and removedfrom the cooling bath. To the still-cold mixture was slowly added HCl(10 mL of a 6M solution), and after stirring 30 min at room temperaturethe layers were separated. The aqueous layer was extracted with CH₂Cl₂(×2), combined organics were washed (water, brine), dried over Na₂SO₄and concentrated in vacuo. The residue was dissolved in PhH (15 mL),along with TsOH.H₂O (0.12 g; 0.64 mmol) and ethylene glycol (3.5 mL; 63mmol), and the solution was heated under reflux for 2 h using aDean-Stark trap to remove water. Upon cooling, the mixture was dilutedwith <solvent>, washed (water, brine), dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash chromatography(EtOAc/hexanes), affording the title compound as a pale yellow oil. ¹HNMR (400 MHz, CDCl₃) δ ppm 4.00-4.11 (m, 2H), 4.11-4.24 (m, 2H), 6.06(s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.99 (s, 1H).

-   Note 1: 4-iodo-2-(trifluoromethyl)benzonitrile is commercially    available from various commercial suppliers; e.g., Apollo Scientific    Ltd, Bredbury, Stockport, Cheshire, UK.

Intermediate I-IX-8:4-(1,3-dioxolan-2-yl)-3-(trifluoromethyl)phenylboronic acid

The title compound was prepared from2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (Example I-IX-7)according to the procedure described for Example V-18, with thefollowing exceptions: the aryl iodide and i-PrMgCl were aged 45 minbefore introduction of the electrophile (instead of 30 min); trimethylborate was used as the electrophile (instead of2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane); the dried organicextracts were concentrated to dryness and triturated with Et₂O/hexanes(instead of flash chromatography). White solid. LC/MS (method A) 2.22min, m/z 417 ({2[M−glycol]−H₂O}−H, 23%), 217 ([M−glycol]−H, 57%), 189(100%, −ve ion).

Formula IX Compounds Example IX-1 4′-formyl-3-biphenylcarboxamide

A mixture of 4-bromobenzaldehyde (2.78 g; 15.0 mmol),[3-(aminocarbonyl)-phenyl]boronic acid (2.72 g; 16.5 mmol),PdCl₂(dppf).CH₂Cl₂ (0.306 g; 0.38 mmol), DME (25 mL) and Na₂CO₃ (25 mLof a 2M solution) was sparged 20 min with N₂ and heated under reflux for90 min (consumption of aryl bromide observed by LC/MS). Upon cooling,the mixture was partitioned between EtOAc/H₂O, layers were separated,and the aqueous layer was extracted with EtOAc (×2). Combined organicswere washed (H₂O, brine), dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash chromatography (EtOAc/hexanes),affording the title compound as a tan solid. LC/MS (method A) 1.91 min,m/z 226 (M+H).

The following examples were prepared from the appropriate arylhalide/triflate and aryl boronic acid/boronate according to theprocedure described for example IX-1, with any significant deviationsnoted below table.

TABLE K Compounds of Formula IX from aryl halides of Formula IV orIntermediates of Formula IX through Suzuki cross-coupling Ex StructureCharacterization Data Comments IX-2 

LC/MS (method A) 1.88 min, m/z 240 (M + H) Used IV-2 and 4- formylphenylboronic acid. IX-3 

LC/MS (method A) 2.13 min; m/z 240 (M + H) Used IV-1 and 4- formylphenylboronic acid. IX-4 

LC/MS (method A) 2.05 min; m/z 240 (M + H) Used 3-(aminocarbonyl)-phenyl boronic acid and I- IX-1. IX-5 

LC/MS (method A) 1.90 min; m/z 226 (M + H) Used 3-(amino-carbonyl)phenyl boronic acid and 3-bromobenz- aldehyde. IX-6 

LC/MS (method A) 1.87 min; m/z 226 (M + H) Used 4-(aminocarbonyl)-phenyl boronic acid and 3- bromobenz-aldehyde. IX-7 

LC/MS (method B) 1.36 min; /z 249 (M + H) Used IV-21 and 4- formylphenylboronic acid Note 1, 2 IX-8 

LC/MS (method A) 1.94 min; /z 256 (M + H) Used 3-(aminocarbonyl)- phenylboronic acid and I- IX-3. Nole 1, 2 IX-9 

LC/MS (method A) 2.09 min; m/z 256 (M + H) Used 3-(aminocarbonyl)-phenyl boronic acid and I- IX-4. Note 1, 2 IX-10

LC/MS (method A) 1.98 min; m/z 244 (M + H) Used 3-(aminocarbonyl)-phenyl boronic acid and I- IX-5. Note 1, 2 IX-11

LC/MS (method A) 2.09 min; m/z 240 (M + H) Used IV-9 and 4- formylphenylboronic acid. IX-12

LC/MS (method B) 1.92 min; m/z 244 (M + H) Used IV-16 and 4-formylphenyl boronic acid. Note 1, 2 IX-13

LC/MS (method B) 1.85 min; m/z 260 (M + H) Used IV-13 and 4-formylphenyl boronic acid. Note 2 IX-14

LC/MS (method B) 2.01 min; m/z 256 (M + H) Used IV-14 and 4-formylphenyl boronic acid. Note 2 IX-15

LC/MS (method A) 1.86 min, m/z 288 (M + H, acetal) 2.02 min; m/z 244(M + H aldehyde) Used IV-6 and 3-fluoro-4- formyl-phenyl boronic acid(Aldrich). Note 2, 7, 10 IX-16

LC/MS (method A) 2.09 min; m/z 240 (M + H) Used 3-(aminocarbonyl)-phenyl boronic acid and I- IX-2 Note 2 IX-17

LC/MS (method A) 1.96 min; m/z 240 (M + H) Used IV-3 and 4- formylphenylboronic acid. Note 2 IX-18

Note 8 Used IV-22 and 3- formylphenyl boronic acid. Nole 2 IX-19

LC/MS (method B) 1.63 min; m/z 227 (M + H) Used 3-(aminocarbonyl)-phenyl boronic acid and 3- formyl-6-bromopyridine. Note 2 IX-20

LC/MS (method B) 2.04 min, m/z 240 (M + H) Used IV-15 and 4-formylphenyl boronic acid. Nole 2 IX-21

LC/MS (method B) 2.27 min; m/z 265 (M + H) Used IV-34 and 4-formylphenyl boronic acid. Note 2, 3 IX-22

Note 9 Used IV-16 and 3-fluoro- 4-formyl-phenyl boronic acid (Aldrich).Note 2, 3 IX-23

LC/MS (method A) 1.99 min; m/z 240 (M + H) Used IV-4 and 3- formylphenylboronic acid. Note 2, 4 IX-24

LC/MS (method A) 1.92 min; m/z 260 (M + H) Used IV-7 and 3- formylphenylboronic acid. Nole 2, 4 IX-25

LC/MS (method A) 1.94 min; m/z 256 (M + H) Used IV-19 and 3-formylphenyl boronic acid. Note 2, 4 IX-26

LC/MS (method A) 2.07 min; m/z 260 (M + H) Used IV-20 and 3-formylphenyl boronic acid. Note 2, 4, 5 IX-27

LC/MS (method A) 1.99 min; m/z 244 (M + H) Used 2-fluoro-5-bromobenzaldehyde and 4-(amino-carbonyl)phenyl boronic acid. Note 2, 4IX-28

LC/MS (method A) 2.05 min; m/z 244 (M + H) Used and 2-fluoro-3-formylboronic acid. Note 2, 4 IX-29

LC/MS (method A) 1.95 min; m/z 244 (M + H) Used 3-bromo-4-fluorobenzaldehyde and 4-(aminocarbonyl phenyl)boronic acid. Nole 2, 4IX-30

LC/MS (method A) 2.25 min; m/z 260 (M + H) Used 3-bromo-5-chlorobenzaldehyde and 4-(aminocarbonyl phenyl)boronic acid. Note 2, 4IX-31

LC/MS (method A) 2.04 min; m/z 258 (M + H) Used IV-4 and 2-fluoro-3-formylphenyl boronic acid. Note 2, 4 IX-32

LC/MS (method B) 1.91 min; m/z 256 (M + H) Used 4-bromo-benzamide and5-formyl-2-methoxy- phenyl boronic acid. Note 2, 4 IX-33

LC/MS (Method E) 0.79 min; m/z 302 (M + H) Note 2 IX-34

LC/MS (Method E) 0.78 min; m/z 265 (M + H) Used IV-35 and 4-formylphenyl boronic acid. IX-35

LC/MS (Method E) 0.73 min; m/z 266 (M + H) Used IV-36 and 4-formylphenyl boronic acid. Nole 2, 6 IX-36

LC/MS (Method E) 0.76 min; m/z 281 (M + H) Used IV-37 and 4-formylphenyl boronic acid. Note 2, 6 IX-37

LC/MS (Method E) 0.81 min; m/z 267 (M + H) Used IV-38 and 4-formylphenyl boronic acid. IX-38

LC/MS (method E) 0.67 min; m/z 303 (M + H) Used IV-39 and 4-formylphenyl boronic acid. IX-39

LC/MS (method A) 1.90 min; m/z 278 (M + H). Used IV-13 and 3-fluoro-4-formyl-phenyl boronic acid (Aidrich) IX-40

LC/MS (method B) 1.54 min; m/z 227 (M + H) Used 5-bromo-2-formylpyridine and 3- (aminocarbonyl)phenyl boronic acid. Note 1 Used4:1 v/v PhMe/EtOH as organic cosolvents (instead of DME). Note 2 UsedPd(PPh₃)₄ as catalyst (instead of PdCl₂(dppf).CH₂Cl₂). Note 3 UsedPd(OAc)₂/S-Phos as catalyst (instead of PdCl₂(dpppf).CH₂Cl₂). Note 4Used acetonitrile/0.4M Na₂CO₃ instead of DME/2M Na₂CO₃. Note 5 UsedK₃PO₄ as base and dioxane as solvent instead of (Na₂CO₃/DME). Note 6Heterocycle N-deprotection (TFA/CH₂Cl₂/RT) immediately following Suzukireaction. Note 7 In several cases, a (dimethyl)acetal and/or hemi-acetalof the title compound was observed by LC/MS, in addition to the expectedtitle compound (presumably formed on the column from MeOH mobile phase,or sample solvent, and TFA mobile phase additive. Note 8 (Ex IX-18) ¹HNMR (400 MHz, DMSO-d6) δ ppm 7.17 (br. s., 3 H), 7.71 (t, J = 7.67 Hz, 1H), 7.84-7.88 (m, 2 H), 7.91 (ddd, J = 7.71, 1.29, 1.16 Hz, 1 H),8.03-8.12 (m, 4 H), 8.07 (d, J = 8.56 Hz, 3 H), 8.28 (t, J = 1.61 Hz, 1H), 10.11 (s, 1 H), 12.62 (br. s., 1 H) Note 9 (Ex IX-22) ¹H NMR (400MHz, DMSO-d6) δ ppm 7.40 (t, J = 7.69 Hz, 1 H), 7.62 (ddd, J = 13.37,1.70, 1.30 Hz, 1 H), 7.65 (dt, J = 17.21, 1.70, 1.35 Hz, 1 H), 7.68-7.75(m, J = 7.65, 7.58, 7.58, 1.74 Hz, 3 H), 7.84 (br. s., 1 H), 7.96 (t, J= 7.69 Hz, 1 H), 10.27 (s, 1 H) Note 10 An alternate preparation ofexample IX-15 is given below.

Example IX-15 3′-fluoro-4′-formyl-3-biphenylcarboxamide (AlternatePreparation)

A 10 mL conical vial equipped with magnetic spin vane was charged with3-bromobenzamide (0.200 g; 1.00 mmol; Ex IV-6), 3-fluoro-4-formyl-phenylboronic acid (0.185 g; 1.1 mmol), tetra-n-butyl ammonium bromide (0.323g; 1.0 mmol), Pd(OAc)₂ (0.0011 g; 0.005 mmol), K₂CO₃ (0.345 g; 2.5 mmol)and sealed with a septum. The vial was evacuated/backfilled withnitrogen (×3), water was added via syringe and the mixture was stirredat 80° C. for 2.5 h. Upon cooling, the mixture was poured into water,layered with Et₂O and sonicated ca. 2 min. Solid was collected byfiltration and washed with Et₂O, affording the title compound as acream-colored solid (used without further purification). LC/MS (methodA) 2.02 min; m/z 244 (M+H).

The following examples were prepared from the appropriate arylhalide/triflate and aryl boronic acid/boronate according to theprocedure described above for example IX-15, with any significantdeviations noted below table.

TABLE L Compounds of Formula IX from Suzuki reaction conditions used inExample IX-15 Ex Structure Characterization Data Comments IX-41

LC/MS (method A) 1.86, 2.02 min; m/z 308 (M + H acetal, 1.86 min) 262(M + H aldehyde, 2.02 min) Used 3- (aminocarbonyl)- phenyl boronic acidand 4-bromo-2,6- difluorobenz-aldehyde. Note 1, 2 IX-42

LC/MS (method A) 2.02, 2.16 min; m/z 308 (M + H acetal, 2.02 min) 260(M - H aldehyde, 2.16 min) Used IV-17 and 3- fluoro-4-formyl-phenylboronic acid (Aldrich). Note 2 IX-43

LC/MS (method B) 2.05 min; m/z 240 (M + H) Used 3-(methyl-carbamoyl)phenyl boronic acid (Combi- Blocks) and 4-bromo- benzaldehyde.IX-44

LC/MS (method A) 2.08, 2 29 min; m/z 306 (M + H acetal, 2.08 min) 260(M - H aldehyde, 2.29 min) Used 3-(amino- carbonyl)phenyl boronic acidand 4- bromo-2-chloro- benzaldehyde. Note 2, 3 Note 14-bromo-2,6-difluorobenzaldehyde is commercially available from varioussuppliers; e.g., Apollo Scientific Ltd., Bredbury, Stockport, Cheshire,UK. Example IX-39 has also been prepared from 3-bromobenzamide (IV-6)and 3,5-difluoro-4-formylphenyl boronic acid (Aldrich), according to theprocedure described for example IX-1, using Pd(OAc)₂/S-Phos as catalystand PhMe/EtOH (4:1) as organic cosolvent. Note 2 In several cases, a(dimethyl)acetal and/or hemi-acetal of the title compound was observedby LC/MS, in addition to the expected title compound (presumably formedon the column from MeOH mobile phase, or sample solvent, and TFA mobilephase additive. Note 3 4-bromo-2-chlorobenzaldehyde is commerciallyavailable from various suppliers; e.g., Apollo Scientific Ltd.,Bredbury, Stockport, Cheshire, UK.

Example IX-45 5-(4-formylphenyl)-3-pyridinecarboxamide

A mixture of 5-bromonicotinamide (0.201 g; 1.00 mmol), 4-formylphenylboronic acid (0.180 g; 1.2 mmol), Pd(OAc)2 (0.0022 g; 0.010 mmol),S-Phos (0.0082 g; 0.020 mmol) and K₂CO₃ (0.345 g; 2.5 mmol) in n-butanol(3 mL) was sparged with nitrogen ca. 10 min, then heated at 80° C. for 1h. Upon cooling, the mixture was poured into water, layered with Et₂Oand sonicated at room temperature ca. 5 min. Solid was collected byfiltration, and the cake was air-dried on the filter, affording thetitle compound as a colorless solid which was used without furtherpurification. LC/MS (method A) 1.57 min; m/z 227 (M+H).

The following examples were prepared from the appropriate arylhalide/triflate and aryl boronic acid/boronate according to theprocedure described for example IX-45, with any significant deviationsnoted below table.

TABLE M Compounds of Formula IX from Suzuki cross-coupling conditionsdescribed in IX-45 Ex Structure/Name Characterization Data CommentsIX-46

LC/MS (method B) (hemiacetal) 1.96 min; m/z 312 (M + H) (aldehyde) 2.08min; m/z 280 (M + H) Used IV-16 and 2,3- difluoro-4-formyl- phenylboronic acid (Aldrich). Note 1, 2, 4 2,2′,3′-trifluoro-4′-formyl-3-biphenylcarboxamide IX-47

LC/MS (method A) (acetal) 2.00 min, m/z 308 (M + H) (aldehyde) 2.12 min;m/z 262 (M + H). Used IV-6 and 2,3- difluoro-4-formyl- phenyl boronicacid (Aldrich). Note 1, 3, 4 2′,3′-difluoro-4′-formyl-3-biphenylcarboxamide IX-48

LC/MS (method A) 2.15 min; m/z 242 (M − H) Used IV-17 and 4-formylphenyl boronic acid. 5-fluoro-4′-formyl-3-biphenyl- carboxamideIX-49

LC/MS (method B) 2.32 min; m/z 260 (M + H) Used IV-8 and 4- formylphenylboronic acid. Note 2 5-chloro-4′-formyl-3- biphenylcarboxamide IX-50

LC/MS (method A) 2.38 min; m/z 292 (M − H) Used IV-10 and 4-formylphenyl boronic acid. 4′-formyl-5-(trifluoromethyl)-3-biphenylcarboxamide IX-51

LC/MS (method A) 1.87 min; m/z 227 (M + H) Used IV-11 and 4-formylphenyl boronic acid. 6-(4-formylphenyl)-2- pyridinecarboxamideIX-52

LC/MS (method A) 1.65 min; m/z 227 (M + H) Used commercially available2-chloro isonicotinamide from Maybridge Building Blocks and4-formylphenyl boronic acid. 2-(4-formylphenyl)-4- pyridinecarboxamideIX-53

LC/MS (method A) 2.03 min; m/z 258 (M + H) Used IV-2 and 3- fluoro-4-formylphenyl boronic acid. (Aldrich). 3′-fluoro-4′-formyl-2-methyl-3-biphenylcarboxamide Note 1 K₃PO₄ was used as base (instead of K₂CO₃),PhMe was used as solvent (instead of n-butanol), reaction temperaturewas 90° C. (instead of 80° C.). Note 2 Product was purified by flashchromatography (EtOAc/hexanes). Note 3 An additional portion of the arylboronic acid (0.5 equiv) was added after 5 h heating. Total reactiontime was 21 h. Note 4 In several cases, the title compounds wereaccompanied by the corresponding (dimethyl)acetals, presumably formed onthe column from MeOH mobile phase (or sample solvent) and the trace acidmobile phase additive (TFA).

Example IX-54 4′-formyl-2′-(trifluoromethyl)-3-biphenylcarboxamide

Step 1: 4′-cyano-2′-(trifluoromethyl)-3-biphenylcarboxamide

The title compound was synthesized from 3-(aminocarbonyl)phenyl boronicacid and 4-iodo-3-(trifluoromethyl)benzonitrile (I-IX-6) according tothe procedure described for Ex IX-10, using Pd(PPh₃)₄ catalyst andPhMe/EtOH (4:1) as organic cosolvents. LC/MS (method A) 2.18 min, m/z291 (M+H).

Step 2: 4′-formyl-2′-(trifluoromethyl)-3-biphenylcarboxamide

To a solution of 4′-cyano-2′-(trifluoromethyl)-3-biphenylcarboxamide(0.239 g; 1.01 mmol; step 1 above) in CH₂Cl₂ (10 mL) at −78° C. wasadded DIBAL-H (2.5 mL of a 1.0M solution in CH₂Cl₂; 2.5 mmol), dropwiseover 3 min. After 15 min the reaction was quenched by addition of 6M HCl(ca. 5 mL), removed from the cooling bath and stirred at roomtemperature for 20 min. The mixture was poured into water and extractedwith CH₂Cl₂ (×3). Combined organics were filtered through a pad ofCelite, washed (satd NaHCO₃, brine), dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatography(EtOAc/hexanes), affording the title compound as a colorless gum. LC/MS(method B) 2.21 min, m/z 294 (M+H).

Example IX-55 4′-formyl-3′-(trifluoromethyl)-1,1′-biphenyl-3-carboxamide

Step 1:4′-(1,3-dioxolan-2-yl)-3′-(trifluoromethyl)-1,1′-biphenyl-3-carboxamide

The title compound was prepared from 3-(aminocarbonyl)phenyl boronicacid and 2-[4-iodo-2-(trifluoromethyl)phenyl]-1,3-dioxolane (I-IX-7)according to the procedure described for IX-10, using PhMe/EtOH (4:1) asorganic cosolvents. Colorless solid. LC/MS (method A) 2.38 min; m/z 338(M+H).

Step 2: 4′-formyl-3′-(trifluoromethyl)-1,1′-biphenyl-3-carboxamide

4′-(1,3-Dioxolan-2-yl)-3′-(trifluoromethyl)-1,1′-biphenyl-3-carboxamide(0.177 g; 0.525 mmol) was added to a solution of HOAc (4 mL) and water(1 mL) and the mixture was stirred at 65° C. in a sealed vial for 1 h.Upon cooling, the mixture was poured into satd NaHCO₃ and extracted withEtOAc (×3). Combined organics were washed (water, brine), dried overNa₂SO₄ and concentrated in vacuo affording the title compound, which wasused without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.55(br. s., 1H), 7.64 (t, J=7.76 Hz, 1H), 7.98 (ddd, J=7.98, 1.38, 1.16 Hz,1H), 8.02 (ddd, J=7.76, 1.87, 1.07 Hz, 1H), 8.18-8.26 (m, 3H), 8.29 (dd,J=8.03, 1.78 Hz, 1H), 8.31 (t, J=1.69 Hz, 1H), 10.31 (q, J=1.96 Hz, 1H)

Example IX-564′-formyl-2-methyl-3′-(trifluoromethyl)-3-biphenyl-carboxamide

Step 1:4′-(1,3-dioxolan-2-yl)-3′-(trifluoromethyl)-3-biphenylcarboxamide

The title compound was prepared from 3-bromo-2-methylbenzamide (Ex IV-2)and 4-(1,3-dioxolan-2-yl)-3-(trifluoromethyl)phenylboronic acid (I-IX-8)according to the procedure described in Example IX-10, using PhMe/EtOH(4:1) as organic cosolvent. LC/MS (method A) 2.36 min; m/z 351 (M+H).

Step 2: 4′-formyl-2-methyl-3′-(trifluoromethyl)-3-biphenylcarboxamide

The title compound was prepared from4′-(1,3-dioxolan-2-yl)-3′-(trifluoromethyl)-3-biphenylcarboxamide (Step1 above) according to the procedure described for example IX-55, Step 2.LC/MS (method A) 2.33 min; m/z 308 (M+H).

Example IX-57 3′-(1H-pyrazol-3-yl)-4-biphenylcarbaldehyde

Step 1: [3-(4′-formyl-3-biphenylyl)-1H-pyrazol-1-yl]methyl2,2-dimethyl-propanoate

The title compound was prepared from3-(3-bromophenyl)-1H-pyrazol-1-yl]methyl 2,2-dimethylpropanoate (ExIV-29) and 4-formylphenyl boronic acid according to the proceduredescribed for IX-10, using PhMe/EtOH (4:1) as organic cosolvents. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.12 (s, 9H), 6.11 (s, 2H), 6.99 (d, J=2.50 Hz,1H), 7.57 (t, J=7.67 Hz, 1H), 7.74 (ddd, J=7.85, 1.96, 1.07 Hz, 1H),7.91 (ddd, J=7.76, 1.61, 1.16 Hz, 1H), 7.96-8.00 (m, 3H), 8.01-8.05 (m,2H), 8.18 (t, J=1.61 Hz, 1H), 10.07 (s, 1H).

Step 2: 3′-(1H-pyrazol-3-yl)-4-biphenylcarbaldehyde

To a solution of [3-(4′-formyl-3-biphenylyl)-1H-pyrazol-1-yl]methyl2,2-dimethyl-propanoate (0.162 g; 0.45 mmol) in 1:1 THF/MeOH (5 mL totalvol) at room temperature was added NaOH (1.1 mL of a 1.0M solution; 1.1mmol). After 30 min, HOAc (0.08 mL; 1.4 mmol) was added and the mixturewas concentrated in vacuo. The residue was partitioned betweenEtOAc/water, layers were separated, the organic layer was washed (satdNaHCO₃, brine), dried over Na₂SO₄ and concentrated in vacuo. The residuewas redissolved in EtOAc, washed (1M HCl, water, brine), dried overNa₂SO₄ and concentrated in vacuo, affording the title compound as aglassy semi-solid which was used without further purification. LC/MS(method A) 2.42 min; m/z 249 (M+H).

Compounds of Formula X

Intermediates of Formula X

The following compounds were employed as precursors of Formula Xcompounds wherein Y is a suitably protected heteroaryl or heterocyclyl,cyano or ester, and at the time of this writing were not readilyavailable from commercial suppliers.

Intermediate I-X-1:3′-[1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazol-3-yl]-4-biphenylcarbaldehydeand3′-[1-({[2-(trimethylsilyl)ethyl]-oxy}methyl)-1H-1,2,4-triazol-5-yl]-4-biphenylcarbaldehyde

A mixture of 4-formylphenyl boronic acid (0.110 g; 0.737 mmol),3-(3-bromophenyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazoleand 5(3-bromophenyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-1,2,4-triazole(0.236 g; 0.667 mmol, Ex V-23), Pd(PPh₃)₄ (0.039 g; 0.033 mmol), 2MNa₂CO₃ (0.80 mL; 1.6 mmol) and PhMe/EtOH (4:1, 8 mL) was sparged with N₂for 10 min and heated under reflux for 16 h. Upon cooling, the mixturewas diluted with EtOAc and washed with water. The aqueous wash wasback-extracted with EtOAc (×2), combined organics were washed (water,brine), dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash chromatography (EtOAc/hexanes), affording the titlecompounds as partially-resolved mixture. LC/MS (method B) isomer 1: 2.97min, m/z 380 (M+H). LC/MS (method B) isomer 2: 3.02 min; m/z 380 (M+H).These regioisomers were combined, and carried on as a mixture.

Intermediate I-X-2:[3-(4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate

A vial equipped with magnetic spin vane was charged with[[3-(3-Bromophenyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate(0.203 g; 0.60 mmol; Ex IV-24), 4-formylphenyl boronic acid (0.099 g;0.66 mmol), and PdCl₂(dppf).CH₂Cl₂ (0.012 g; 0.015 mmol), was sealedwith a septum and evacuated/backfilled with N₂ (×3). PhMe/EtOH (4:1, 3mL) and 2M Na₂CO₃ (0.72 mL; 1.44 mmol) were added through the septum viasyringe and the mixture was stirred at 80° C. for 2.5 h. Upon cooling,the mixture was partitioned between EtOAc/water and the layers wereseparated. The aqueous layer was extracted with EtOAc (×2), combinedorganics were washed (water, brine), dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by flash chromatography(EtOAc/hexanes), affording the title compound as a colorless gum/film.LC/MS (method A) 2.60 min; m/z 364 (M+H).

The following intermediates were prepared from the appropriate arylhalide/triflate and aryl boronic acid/boronate ester according to theprocedure described for intermediate I-X-2, with any significantdeviation noted below table.

TABLE N Compounds of Formula X from Suzuki cross-coupling similar tothat described in I-X-2 Ex Structure/Name Characterization Data CommentsI-X-3

LC/MS (method B) 2.76 min; m/z 364 (M + H) Used IV-33 and 4-formylphenyl boronic acid. [4-(4′-formyl-3-biphenylyl)-1H-1,2,3-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-4

LC/MS (method A) acetal: 2.58 min; m/z 448 (M + H) aldehyde: 2.74 min;m/z 416 (M + H) Used IV-28 and 3- fluoro-4-formyl-phenyl boronic acidNote 1 [3-(2-chloro-3′-fluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-5

LC/MS (method A) 2.7 min; m/z 378 (M + H) Used IV-27 and 4- formylphenylboronic acid. [3-(4′-formyl-2-methyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2- dimethylpropanoate I-X-6

LC/MS (method A) 2.65 min; m/z 382 (M + H) Used IV-26 and 4-formylphenyl boronic acid. [3-(2-fluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2- dimethylpropanoate I-X-7

LC/MS (method A) 2.63 min; m/z 398 (M + H) Used IV-28 and 4-formylphenyl boronic acid. [3-(2-chloro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2- dimethylpropanoate I-X-8

LC/MS (method A) hemiacetal: 2.67 min; m/z 414 (M + H); aldehyde: 2.85min; m/z 382 (M + H). Used IV-24 and 3- fluoro-4-formyl-phenyl boronicacid. Note 1 [3-(3′-fluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2- dimethylpropanoate I-X-9

Note 2 Used IV-24 and 3,5- difluoro-4-formyl- phenyl boronic acid. Note2 [3-(3′,5′-difluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2- dimethylpropanoate I-X-10

Note 4 Used IV-30 and 2- fluoro-3-formyl-phenyl boronic acid. Note 3[3-(2′-fluoro-3′-formyl-4-biphenylyl)-1H- 1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-11

Note 5 Used IV-32 and 2- fluoro-3-formyl phenyl boronic acid. Note 3Also prepared by microwave heating.[3-(2,2′-difluoro-3′-formyl-4-biphenylyl)- 1H-1,2,4-triazol-1-yl]methyl2,2- dimethylpropanoate I-X-12

Note 6 Used IV-31 and 2- fluoro-3-formylphenyl boronic acid. Note 3[3-(2′-fluoro-5′-formyl-2-methyl-4-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-13

Note 7 Used IV-30 and 2,4- difluoro-3-formyl phenyl boronic acid. Note 3[3-(2′,4′-difluoro-3′-formyl-4-biphenylyl)- 1H-1,2,4-triazol-1-yl]methyl2,2- dimethylpropanoate I-X-14

Note 8 Used IV-24 and 2,4- difluoro-3- formylphenyl boronic acid. Note 3[3-(2′,4′-difluoro-3′-formyl-3-biphenylyl)- 1H-1,2,4-triazol-1-yl]methyl2,2- dimethylpropanoate I-X-15

LC/MS (method B) 0.87 min; m/z 382 (M + 1) Used IV-24 and 3-formylphenyl boronic acid. Note 3[3-(2′-fluoro-3′-formyl-3-biphenylyl)-1H- 1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-16

LC/MS (method B) 0.88 min; m/z 382 (M + 1) Used IV-24 and 4-fluoro-3-formyl-phenyl boronic acid. Note 3[3-(4′-fluoro-3′-formyl-3-biphenylyl)-1H- 1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate Note 1 In several cases, a (dimethyl)acetal and/orhemi-acetal of the title compound was observed by LC/MS, in addition tothe expected title compound; presumably formed on the column from MeOHmobile phase, or sample solvent, and TFA mobile phase additive. Note 2Pd(OAc)₂/S—Phos was used as catalyst. An alternate preparation of I-X-8is given below. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13 (s, 9 H), 6.21 (s,2 H), 7.65 (app. t, J = 7.94 Hz, 1 H), 7.67-7.72 (m, 2 H), 7.91 (app.ddd, J = 7.85, 1.96, 1.07 Hz, 1 H), 8.13 (app. dd, J = 7.94, 1.34 Hz, 1H), 8.34 (app. t, J = 1.52 Hz, 1 H), 8.83 (s, 1 H), 10.25 (s, 1 H). Note3 Used 2 equiv aryl boronic acid. Note 4 1H NMR (400 MHz, CDCl3) δ ppm1.20 (s, 9 H), 6.10 (s, 2 H), 7.35 (t, J = 7.69 Hz, 1 H), 7.60-7.69 (m,2 H), 7.74 (td, J = 7.51, 1.83 Hz, 1 H), 7.84-7.92 (m, 1 H), 8.23 (d, J= 8.30 Hz, 2 H), 8.39 (s, 1 H), 10.46 (s, 1 H). Note 5 (I-X-11) 1H NMR(400 MHz, CDCl3) δ ppm 1.19 (s, 9 H), 6.09 (s, 2 H), 7.36 (t, J = 7.69Hz, 1 H), 7.48 (t, J = 7.69 Hz, 1 H), 7.68 (t, J = 6.84 Hz, 1 H),7.88-8.07 (m, 3 H), 8.39 (s, 1 H), 10.44 (s, 1 H). Note 6 (I-X-12) 1HNMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9 H), 2.28 (s, 3 H), 6.10 (s, 2 H),7.27-7.39 (m, 2 H), 7.54 (td, J = 7.20, 1.46 Hz, 1 H), 7.85-7.94 (m, 1H), 8.02 (d, J = 8.06 Hz, 1 H), 8.09 (s, 1 H), 8.38 (s, 1 H), 10.43 (s,1 H). Note 7 (I-X-13) 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9 H), 6.09(s, 2 H), 7.09 (t, J = 9.16 Hz, 1 H), 7.59 (d, J = 6.84 Hz, 2 H), 7.69(td, J = 8.48, 6.23 Hz, 1 H), 8.22 (d, J = 8.30 Hz, 2 H), 8.38 (s, 1 H),10.43 (s, 1 H). Note 8 (I-X-14) 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9H), 6.09 (s, 2 H), 7.08 (t, J = 9.28 Hz, 1 H), 7.53-7.59 (m, 2 H), 7.73(td, J = 8.48, 6.23 Hz, 1 H), 8.14-8.21 (m, 1 H), 8.25 (s, 1 H), 8.39(s, 1 H), 10.43 (s, 1 H).

Alternate Preparation of Intermediate I-X-9:[3-(3′,5′-difluoro-4′-formyl-3-biphenyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate

A flask was charged with PhMe/EtOH (4:1, 50 mL), water (25 mL) andNaHCO₃ (3.78 g; 45 mmol) and the mixture was sparged with N₂ for 15 minin an ultrasonic bath. [3-(3-bromophenyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate (5.07 g; 15.0 mmol; Ex IV-24),3,5-difluoro-4-formyl-phenyl boronic acid (3.07 g; 16.5 mmol) andPdCl₂(dppf).CH₂Cl₂ (0.245 g; 0.30 mmol) were added in one portion andthe mixture was heated under reflux for 10 h. Upon cooling, solids werecollected by filtration, washed (Et₂O/hexane), dissolved in hot EtOAcand filtered without delay through a short pad of silica get (1:1EtOAc/hexanes eluent). Filtrate collected from the reaction mixture wasdiluted with water/EtOAc, separated and the aqueous layer extracted withEtOAc (×3). Combined organics were washed (water, brine), dried overNa₂SO₄ and concentrated in vacuo. The residue obtained from the extractswas dissolved in hot EtOAc, filtered through silica (1:1 EtOAc/hexaneseluent), and the filtrate combined with that obtained from the crudereaction mixture solids. Combined filtrates were concentrated in vacuo,affording the title compound as a pale yellow solid.

In another preparation of the title compound, Pd(OAc)₂/S-Phos(0.005/0.010 equiv) were used as catalyst, NaHCO₃ (3 equiv) was used asbase, and PhMe/water were used as solvents (without EtOH additive),reaction time 3 h/85° C. Product I-X-9 was isolated in a manneranalogous to the above procedure.

Choice of base appears to be a key parameter in the cross-coupling ofEx. IV-24 under typical biphasic conditions. In our hands, NaHCO₃ was aneffective and reliable base for preparation of I-X-9. On some occasions,the use of Na₂CO₃, as base resulted in stalled reactions; mixtures ofIV-24 and I-X-9 were returned, accompanied by varying amounts ofdeprotected IV-24 (i.e., 3-bromo phenyl-1H-1,2,4-triazole).

Intermediate I-X-17:[3-(3′-formyl-4-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate

To a solution of [3-(4-bromophenyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethyl-propanoate (0.108 g, 0.32 mmol; IV-30), 3-formylphenylboronic acid (0.099 g, 0.66 mmol), and PdCl₂(dppf).CH₂Cl₂ (0.024 g,0.029 mmol) was added 2M Na₂CO₃ (aq) (0.38 mL, 0.76 mmol). The mixturewas subjected to microwave heating (135° C./50 min), cooled, andpartitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc, combined organic extracts were dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash chromatography(EtOAc/hexanes), affording the title compound as a colorless solid. ¹HNMR (400 MHz, CDCl3)

ppm 1.20 (s, 9H), 6.10 (s, 2H), 7.63 (t, J=7.69 Hz, 1H), 7.73 (d, J=8.06Hz, 2H), 7.90 (dd, J=14.65, 7.57 Hz, 2H), 8.15 (m, 1H), 8.23 (d, J=8.30Hz, 2H), 8.39 (s, 1H), 10.10 (s, 1H).

The following intermediates were prepared from the appropriate arylhalide/triflate and aryl boronic acid/boronate ester according to theprocedure described for intermediate I-X-17, with any significantdeviation noted below table.

TABLE O Compounds of Formula X from Suzuki cross-coupling similar tothat described in I-X-17 Ex Structure/Name Characterization DataComments I-X-18

Note 1 Used IV-30 and (4- fluoro-3-formyl- phenyl)boronic acid. (140°C./40 min). [3-(4′-fluoro-3′-formyl-4-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2- dimethylpropanoate I-X-19

Note 2 Used IV-30 and 2- fluoro-3-formyl-phenyl boronic acid. Note 5.[3-(2′-fluoro-3′-formyl-4-biphenylyl)-1H- 1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-20

Note 3 Used IV-31 and 3- formylphenyl boronic acid. (140° C./1 h)[3-(3′-formyl-2-methyl-4-biphenylyl)- 1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate I-X-21

Note 4 Used IV-32 and 3- formylphenyl boronic acid. (140° C./40 min).[3-(2-fluoro-3′-formyl-4-biphenylyl)-1H- 1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate Note 1 (I-X-18) 1H NMR (400 MHz, CDCl3) δ ppm 1.20(s, 9 H), 6.09 (s, 2 H), 7.25-7.31 (m, 1 H), 7.66 (d, J = 8.06 Hz, 2 H),7.87 (m, 1 H), 8.13 (dd, J = 6.47, 2.32 Hz, 1 H), 8.21 (d, J = 8.30 Hz,2 H), 8.38 (s, 1 H), 10.43 (s, 1 H). Note 2 (I-X-19) 1H NMR (400 MHz,CDCl3) δ ppm 1.20 (s, 9 H), 6.10 (s, 2 H), 7.35 (t, J = 7.69 Hz, 1 H),7.65 (d, J = 7.32 Hz, 2 H), 7.74 (t, J = 6.84 Hz, 1 H), 7.83-7.93 (m, 1H), 8.23 (d, J = 8.30 Hz, 2 H), 8.39 (s, 1 H), 10.46 (s, 1 H). Note 3(I-X-20) 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9 H), 2.33 (s, 3 H),6.10 (s, 2 H), 7.32 (d, J = 8.06 Hz, 1 H), 7.56-7.66 (m, 2 H), 7.82-7.92(m, 2 H), 8.01 (d, J = 8.06 Hz, 1 H), 8.07 (s, 1 H), 8.38 (s, 1 H),10.07 (s, 1 H). Note 4 (I-X-21) 1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9H), 6.09 (s, 2 H), 7.56 (t, J = 7.93 Hz, 1 H), 7.63 (t, J = 7.69 Hz, 1H), 7.85-7.98 (m, 3 H), 8.01 (d, J = 8.06 Hz, 1 H), 8.10 (s, 1 H), 8.39(s, 1 H), 10.09 (s, 1 H). Note 5 100° C./10 min, then 120° C./20 min.Additional boronic acid and catalyst were added, and heating resumed;120° C./20 min, then 135° C./30 min.

Intermediate I-X-22:1,1-dimethylethyl[(3′-amino-3,5-difluoro-4-biphenylyl)-methyl]2,3-dihydro-1H-inden-2-ylcarbamate

Step 1:N-[(3,5-difluoro-3′-nitro-4-biphenylyl)methyl]-2,3-dihydro-1H-inden-2-amine

A mixture of{4-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3,5-difluoro-phenyl}boronicacid (740 mg, 2.44 mmol; Ex V-22), 3-bromonitrobenzene (495 mg, 2.44mmol), PdCl₂(dppf)₂ (100 mg, 0.12 mmol) and Na₂CO₃ (4.90 mL, 2.0 M (aq))in DME (10 mL) was stirred at 80° C. for 45 min. The mixture was dilutedwith EtOAc then filtered through a pad of Celite and silica gel. Thefiltrate was washed with H₂O and brine, dried over Na₂SO₄ thenconcentrated to giveN-[(3,5-difluoro-3′-nitro-4-biphenylyl)methyl]-2,3-dihydro-1H-inden-2-amineas a tan glass. LC/MS (method A) 0.62 min, (m/z) 381 (70%), 382 (100%).

Step 2:1,1-dimethylethyl[(3′-amino-3,5-difluoro-4-biphenylyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate

A solution ofN-[(3,5-difluoro-3′-nitro-4-biphenylyl)methyl]-2,3-dihydro-1H-inden-2-amine(920 mg, 2.42 mmol; step 1), (Boc)₂O (630 mg, 2.90 mmol), andtriethylamine (1.70 mL, 12.1 mmol) in THF (10 mL) was stirred at roomtemperature for 16 hr. The solution was diluted with EtOAc, washed withH₂O and brine, dried over Na₂SO₄ then concentrated. To the residue wasadded THF (10 mL) and Pd/C (100 mg) and the mixture stirred vigorouslyat room temperature under 1 atm H₂ for 45 min. The mixture was filteredthrough a pad of Celite and silica gel then concentrated to give1,1-dimethylethyl[(3′-amino-3,5-difluoro-4-biphenylyl)methyl]2,3-dihydro-1H-inden-2-ylcarbamate

as a tan glass. LC/MS (method A) 1.02 min, (m/z) 451 (M+1).

Compounds of Formula X Example X-1 ethyl4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]-benzoate

To a 100 mL round bottom flask was added ethyl4-(5-formyl-2-furanyl)benzoate (100 mg, 0.41 mmol, commerciallyavailable), [2-(3-fluorophenyl)ethyl]amine (0.070 mL, 0.49 mmol),NaBH(OAc)₃ (261 mg, 1.23 mmol) and DCE (10 mL). The reaction was stirredat room temperature overnight, quenched with H₂O, and extracted withCH₂Cl₂ (×3). The organic layer was washed with brine, dried with MgSO₄and concentrated under reduced pressure to give 150 mg of ethyl4-[5-({[2-(3-fluorophenyl)-ethyl]amino}methyl)-2-furanyl]benzoate (usedwithout further purification). LC/MS (method A) 1.97 min; m/z 368 (M+H).

The following examples were prepared from ethyl4-(5-formyl-2-furanyl)benzoate and the appropriate compounds of FormulaIII according to the procedure described in Ex X-1, with any significantdeviations noted below table.

TABLE P Compounds of Formula X from reductive alkylation ofIntermediates of Formula X Ex. Structure/Name Characterization DataComments X-2

LC/MS (method B) 1.95 min, m/z 316. ethyl 4-(5-{[(3-methylbutyl)-amino]methyl}-2-furyl)benzoate

Example X-3(3-{3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-4-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl2,2-dimethylpropanoate

To a solution of[3-(3′-formyl-4-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate (0.081 g, 0.22 mmol; I-X-17) and 2-aminoindane(0.045 mL, 0.35 mmol) in 1:1 THF/MeOH (2 mL) was added acetic acid (0.12mL) and MP-BH₃CN (ca. 0.67 mmol, Note 1). The mixture was stirred atroom temperature overnight, resin was remove by filtration (THF wash)and the filtrate was concentrated in vacuo. The residue was partitionedbetween EtOAc/5% Na₂CO₃, layers were separated and the aqueous layer wasextracted with EtOAc. Combined organics were washed (water, brine),dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby flash chromatography (MeOH/CH₂Cl₂), affording the title compound. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.20 (s, 9H), 2.84 (dd, J=15.6, 6.4 Hz, 2H),3.20 (dd, J=15.6, 7.1 Hz, 2H), 3.68-3.75 (m, 1H), 3.93 (s, 2H), 6.09 (s,2H), 7.08-7.23 (m, 4H), 7.31-7.38 (m, 1H), 7.41 (t, J=7.6 Hz, 1H), 7.53(d, J=7.6 Hz, 1H), 7.63 (s, 1H), 7.69 (d, J=8.3 Hz, 2H), 8.19 (d, J=8.3Hz, 2H), 8.37 (s, 1H).

-   Note ‘MP-BH₃CN’=macroporous polymer-supported trialkylammonium    cyanoborohydride (Argonaut Technologies).

The following examples were prepared from the appropriate intermediatesof formula X and compounds of Formula III according to the proceduredescribed in Ex X-3, with any significant deviations noted below table.

TABLE Q Compounds of Formula X from reductive alkylation ofIntermediates of Formula X having an N-protected heterocycle ExStructure/Name Characterization Data Comments X-4

1H NMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9H), 2.84 (dd, J = 15.38, 6.35Hz, 2H), 3.20 (dd, J = 15.63, 7.08 Hz, 2H), 3.66- 3.75 (m, 1H), 3.97 (s,2H), 6.08 (s, 2H), 7.06-7.23 (m, 5H), 7.45-7.53 (m, 1H), 7.62-7.64 (d +m, 3H), 8.17 (d, J = 8.30 Used I-X-18 (3-{3′-[(2,3-dihydro-1H-inden-2-Hz, 2H), 8.37 (s, 1H) ylamino)methyl]-4′-fluoro-4-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl 2,2- dimethylpropanoate X-5

1H NMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9H), 2.83 (dd, J = 15.50, 6.47Hz, 2H), 3.20 (dd, J = 15.50, 6.96 Hz, 2H), 3.67- 3.73 (m, 1H), 3.98 (s,2H), 6.09 (s, 2H), 7.08-7.22 (m, 5H), 7.37 (t, J = 7.32 Hz, 2H), 7.63(d, J = 7.08 Hz, 2H), 8.19 (d, Used I-X-19(3-{3′-[(2,3-dihydro-1H-inden-2- J = 8.30 Hz, 2H), 8.37ylamino)methyl]-2′-fluoro-4-biphenylyl}- (s, 1H)1H-1,2,4-triazol-1-yl)methyl 2,2- dimethylpropanoate X-6

1H NMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9H), 2.33 (s, 3H), 2.82 (dd, J =15.50, 6.47 Hz, 2H), 3.18 (dd, J = 15.38, 7.08 Hz, 2H), 3.67-3.74 (m,1H), 3.91 (s, 2H), 6.09 (s, 2H), 7.08-7.23 (m, 5H), 7.28-7.41 (m, 4H),7.97 (d, J = 7.81 Hz, 1H), 8.03 Used I-X-20(3-{3′-[(2,3-dihydro-1H-inden-2- (s, 1H), 8.37 (s, 1H)ylamino)methyl]-2-methyl-4- biphenylyl}-1H-1,2,4-triazol-1-yl)methyl2,2-dimethylpropanoate X-7

(M + 1) 489.3 AP, 2.27 min (LC/MS Method B) Used I-X-20 and III-1. Note1 [3-(3′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2-methyl-4-biphenylyl)-1H-1,2,4-triazol- 1-yl]methyl2,2-dimethylpropanoate X-8

(M + 1) 489.3 AP, 2.34 min (LC/MS Method B) Used I-X-20 and III-7. Note1 [3-(3′-{[(2- cyclohexylethyl)amino]methyl}-2-methyl-4-biphenylyl)-1H-1,2,4-triazol- 1-yl]methyl2,2-dimethylpropanoate X-9

1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9H), 2.83 (dd, J = 15.50, 6.47Hz, 2H), 3.19 (dd, J = 15.63, 7.08 Hz, 2H), 3.68- 3.75 (m, 1H), 3.93 (s,2H), 6.09 (s, 2H), 7.09-7.22 (m, 4H), 7.34-7.45 (m, 2H), 7.45-7.60 (m,3H), 7.88-7.93 (m, 1H), Used I-X-21. (3-{3′-[(2,3-dihydro-1H-inden-2-7.96 (d, J = 8.06 Hz, ylamino)methyl]-2-fluoro-4-biphenylyl}- 1H), 8.38(s, 1H) 1H-1,2,4-triazol-1-yl)methyl 2,2- dimethylpropanoate X-10

(M + 1) 493.3 AP, 2.31 min (LC/MS Method B) Used I-X-21 and III-1. Note1 [3-(3′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2-fluoro-4-biphenylyl)-1H-1,2,4-triazol-1- yl]methyl2,2-dimethylpropanoate X-11

(M + 1) 493.3 AP, 2.34 min (LC/MS Method B) Used I-X-21 and III-7. Note1 [3-(3′-{[(2- cyclohexylethyl)amino]methyl}-2-fluoro-4-biphenylyl)-1H-1,2,4-triazol-1- yl]methyl2,2-dimethylpropanoate X-12

1H NMR (400 MHz, CDCl3) δ ppm 1.20 (s, 9H), 2.83 (dd, J = 15.50, 6.23Hz, 2H), 3.19 (dd, J = 15.63, 7.08 Hz, 2H), 3.66- 3.72 (m, 1H), 3.98 (s,2H), 6.09 (s, 2H), 7.08-7.23 (m, 5H), 7.32 (t, J = 6.84 Hz, 1H),7.38-7.51 (m, 2H), 7.92 (dd, J = 10.99, Used I-X-11. Note 3(3-{3′-[(2,3-dihydro-1H-inden-2- 1.22 Hz, 1H), 7.97 (d,ylamino)methyl]-2,2′-difluoro-4- J = 8.06 Hz, 1H), 8.38biphenylyl}-1H-1,2,4-triazol-1-yl)methyl (s, 1H) Impurity2,2-dimethylpropanoate present in NMR— material used in the nextreaction without further purification. X-13

1H NMR (400 MHz, CDCl3) δ ppm 0.89 (s, 3H), 0.90 (s, 3H), 1.12-1.26 (s +m, 11H), 1.27-1.45 (m, 4H), 1.71-1.80 (m, 2H), 2.41-2.52 (m, 1H), 3.88(s, 2H), 6.09 (s, 2H), 7.32 (d, J = 7.32 Hz, 1H), 7.40 (t, J = 7.57 Hz,1H), 7.52 (d, J = 7.57 Hz, 1H), Used I-X-17 and III-1. Note 1[3-(3′-{[(4,4- 7.58 (s, 1H), 7.69 (d,dimethylcyclohexyl)amino]methyl}-4- J = 8.30 Hz, 2H), 8.18biphenylyl)-1H-1,2,4-triazol-1-yl]methyl (d, J = 8.06 Hz, 2H),2,2-dimethylpropanoate 8.37 (s, 1H) X-14

1H NMR (400 MHz, CDCl3) δ ppm 0.89 (s, 3H), 0.90 (s, 3H), 1.08-1.26 (s +m, 11H), 1.26-1.45 (m, 4H), 1.67-1.81 (m, 2H), 2.38-2.50 (m, 1H), 3.92(s, 2H), 6.09 (s, 2H), 7.17 (t, J = 7.57 Hz, 1H), 7.28- 7.41 (m, 2H),7.63 (d, J = 8.06 Hz, 2H), Used I-X-19 and III-1. Note 1 [3-(3′-{[(4,4-8.19 (d, J = 8.30 Hz, dimethylcyclohexyl)amino]methyl}-2′- 2H), 8.37 (s,1H) fluoro-4-biphenylyl)-1H-1,2,4-triazol-1- yl]methyl2,2-dimethylpropanoate X-15

(M + 1) 493.2 AP, 0.75 min (LC/MS Method B, gradient time = 1.5 min)Used I-X-19 and III-7. Note 1 [3-(3′-{[(2-cyclohexylethyl)amino]methyl}-2′-fluoro-4-biphenylyl)-1H-1,2,4-triazol-1- yl]methyl2,2-dimethylpropanoate X-16

Not characterized (Note 2) Used I-X-11 and III-1. Note 1, 2[3-(3′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2,2′-difluoro-4-biphenylyl)-1H-1,2,4-triazol- 1-yl]methyl2,2-dimethylpropanoate X-17

(M + 1) 513.3 AP, 0.71 min (LC/MS Method B, gradient time = 1.5 min)Used I-X-12 and III-1. Note 3 (3-{3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2′-fluoro-2-methyl-4-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl 2,2-dimethylpropanoate X-18

Not characterized (Note 2) Used I-X-12 and III-1. Note 2 [3-(3′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2′-fluoro-2-methyl-4-biphenylyl)-1H-1,2,4- triazol-1-yl]methyl 2,2-dimethylpropanoate X-19

(M + 1) 517.2 AP, 0.69 min (LC/MS Method B, gradient time = 1.5 min)Used I-X-13. (3-{3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2′,4′-difluoro-4-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl 2,2-dimethylpropanoate X-20

Not characterized (Note 2) Used I-X-13 and III-1. Note 1, 2[3-(3′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2′,4′-difluoro-4-biphenylyl)-1H-1,2,4- triazol-1-yl]methyl 2,2-dimethylpropanoate X-21

1H NMR (400 MHz, CDCl3) δ ppm 1.19 (s, 9H), 2.82 (dd, J = 15.63, 6.35Hz, 2H), 3.18 (dd, J = 15.50, 6.96 Hz, 2H), 3.62- 3.69 (m, 1H), 4.03 (s,2H), 6.08 (s, 2H), 6.97 (t, J = 8.55 Hz, 1H), 7.09-7.16 (m, Used I-X-14.(3-{3′-[(2,3-dihydro-1H-inden-2- 2H), 7.16-7.23 (m,ylamino)methyl]-2′,4′-difluoro-3- 2H), 7.35-7.43 (m,biphenylyl}-1H-1,2,4-triazol-1-yl)methyl 1H), 7.49-7.59 (m,2,2-dimethylpropanoate 2H), 8.13 (d, J = 7.08 Hz, 1H), 8.26 (s, 1H),8.37 (s, 1H) X-22

1H NMR (400 MHz, CDCl3) ppm 0.89 (s + s, 6H), 1.12-1.27 (s + m, 11H),1.27 - 1.45 (m, 4H), 1.69 - 1.81 (m, 2H), 2.34 - 2.45 (m, 1H), 3.97 (s,2H), 6.08 (s, 2H), Used I-X-14 and III-1. Note 1,4 (3-(3′-((4,4- 6.95(t, J = 8.55 Hz, dimethylcyclohexylamino)methyl)-2′,4′- 1H), 7.33-7.42(m, difluorobiphenyl-3-yl)-1H-1,2,4-triazol- 1H), 7.48-7.60 (m,1-yl)methyl pivalate 2H), 8.12 (d, J = 7.32 Hz, 1H), 8.25 (s, 1H), 8.37(s, 1H) X-23

Not characterized (Note 2) Used I-X-14 and III-7. Note 1, 2, 4[3-(3′-{[(2- cyclohexylethyl)amino]methyl}-2′,4′-difluoro-3-biphenylyl)-1H-1,2,4-triazol- 1-yl]methyl2,2-dimethylpropanoate X-24

(M + 1) 499.2 AP, 0.80 min (LC/MS Method B, gradient time = 1.5 min))Used I-X-15. Note 4 (3-{3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2′-fluoro-3- biphenylyl}-1H-1,2,4-triazol-1-yl)methyl2,2-dimethylpropanoate X-25

(M + 1) 499.2 AP, 0.82 min (LC/MS Method B, gradient time = 1.5 min)Used I-X-16. Note 4 (3-{3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-4′-fluoro-3- biphenylyl}-1H-1,2,4-triazol-1-yl)methyl2,2-dimethylpropanoate X-26

Not characterized (Note 2) Used I-X-1 and III-3. Note 1, 24,4-dimethyl-N-((3′-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)biphenyl-4- yl)methyl)cyclohexanamine and 4,4-dimethyl-N-((3′-(1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)biphenyl-4- yl)methyl)cyclohexanamine X-27

Not characterized (Note 2) Used I-X-1 Note 1, 2 N-((3′-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)biphenyl-4-yl)methyl)-2,3- dihydro-1H-inden-2-amine andN-((3′- (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)biphenyl-4- yl)methyl)-2,3-dihydro-1H-inden-2-amine X-28

LC/MS (method A) 2.25 min; m/z 475 (M + H) Used I-X-3 and III-1 Note 1[4-(4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-3-biphenylyl)-2H-1,2,3-triazol-2-yl]methyl 2,2-dimethylpropanoate X-29

LC/MS (method A) 2.11 min; m/z 482 (M + H) Used I-X-3 Note 1(4-{4′-[(2,3-dihydro-1H-inden-2- ylamino)methyl]-3-biphenylyl}-2H-1,2,3-triazol-2-yl)methyl 2,2- dimethylpropanoate X-30

Not characterized (Note 2) Used I-X-6 Note 1, 2, 5(3-{4′-[(2,3-dihydro-1H-inden-2- ylamino)methyl]-2-fluoro-3-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl 2,2- dimethylpropanoate X-31

Not characterized (Note 2) Used I-X-7 Note 1, 2, 5(3-{2-chloro-4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-1H- 1,2,4-triazol-1-yl)methyl 2,2-dimethylpropanoate X-32

Note 5 Used I-X-8 Note 1, 5 (3-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3′-fluoro-3-biphenylyl}- 1H-1,2,4-triazol-1-yl)methyl2,2- dimethylpropanoate X-33

Note 6 Used I-X-9 Note 1, 2, 5, 6 (3-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3′,5′-difluoro-3-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl 2,2-dimethylpropanoate X-34

LC/MS (method E) 0.79 min; m/z 499 (M + H) Used I-X-2 and (S)-III- 11Note 1, 7 {3-[4′-({[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3- biphenylyl]-1H-1,2,4-triazol-1-yl}methyl2,2-dimethylpropanoate X-35

LC/MS (method E) 0.79 min; m/z 499 (M + H) Used I-X-2 and (R)-III- 11Note 1, 7 {3-[4′-({[(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3- biphenylyl]-1H-1,2,4-triazol-1-yl}methyl2,2-dimethylpropanoate X-36

LC/MS (method E) 0.85 min; m/z 511 (M + H) Used I-X-9 and III-1 Note 1,8 [3-(4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-3′,5′-difluoro-3-biphenylyl)-1H-1,2,4- triazol-1-yl]methyl 2,2-dimethylpropanoate X-37

LC/MS (method E) 0.84 min; m/z 535 (M + H) Used I-X-9 and (R)-III- 11Note 1, 8 {3-[3′,5′-difluoro-4′-({[(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)- 3-biphenylyl]-1H-1,2,4-triazol-1-yl}methyl 2,2-dimethylpropanoate X-38

LC/MS (method E) 0.84 min; m/z 535 (M + H) Used I-X-9 and (S)-III- 11Note 1, 8 {3-[3′,5′-difluoro-4′-({[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)- 3-biphenylyl]-1H-1,2,4-triazol-1-yl}methyl 2,2-dimethylpropanoate X-39

LC/MS (method E) 1.05 min; m/z 547 (M + H) Used I-X-9 and III-8 Note 1,8 [3-(4′-{[(2-cyclohexyl-2,2- difluoroethyl)amino]methyl}-3′,5′-difluoro-3-biphenylyl)-1H-1,2,4-triazol- 1-yl]methyl2,2-dimethylpropanoate X-40

LC/MS (method E) 0.87 min; m/z 511 (M + H) Used I-X-9 and III-7 Note 1,8 [3-(4′-{[(2- cyclohexylethyl)amino]methyl}-3′,5′-difluoro-3-biphenylyl)-1H-1,2,4-triazol- 1-yl]methyl2,2-dimethylpropanoate X-41

LC/MS (method E) 0.82 min; m/z 491 (M + H) Used I-X-9 Note 8[3-(3′,5-difluoro-4′- {[(phenylmethyl)amino]methyl}-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate X-42

LC/MS (method E) 83 min; m/z 505 (M + H) Used I-X-9 Note 8[3-(3′,5′-difluoro-4′-{[(2- phenylethyl)amino]methyl}-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate X-43

LC/MS (method E) 0.84 min; m/z 519 (M + H) Used I-X-9 Note 8[3-(3′,5′-difluoro-4′-{[(3- phenylpropyl)amino]methyl}-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl 2,2-dimethylpropanoate X-44

LC/MS (method E) 0.88 min; m/z 537 (M + H) Used I-X-9 Note 8{3-[3′,5′-difluoro-4′-({[(1R,2R,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]amino}methyl)-3-biphenylyl]-1H-1,2,4-triazol-1-yl}methyl 2,2- dimethylpropanoate Note 1 The aminehydrochloride salt used was admixed with an equimolar amount of Et₃N inTHF/MeOH before use. Note 2 In some cases, particularly on small-scalepreparations, the compound of Formula X shown in the above table wascarried onto the deprotection step without characterization (en route toFormula I). Note 3 Title compound was purified by preparative HPLC (C-18column, MeCN/water gradient with 0.1% TFA additive). Note 4 Solutionphase reductive amination conditions were used: 1.5 equiv eaamine/amine•HCl—Et₃N (Note 1) and NaBH(OAc)₃, ca. 5% v/v HOAc/CH₂Cl₂solvent, room temperature. Formula X product purified by flashchromatography (CH₂Cl₂/MeOH). Note 5 Purified by flash chromatographyusing amine-functionalized silica gel (Teledyne-Isco # 68-2203-102,EtOAc/hexanes). Note 6 Characterizing data for X-33 is given in thealternate preparation below. Note 7 Title compounds also prepared usingsolution phase reductive amination conditions: 1.1 equiv eaamine•HCl—Et₃N (Note 1) and NaBH₃CN, ca. 5% v/v HOAc in MeOH as solvent,room temperature. Formula X product was purified by flash chromatographyusing amine-functionalized silica gel (Teledyne-Isco # 68-2203-102,EtOAc/hexanes). Note 8 1:1 CH₂Cl₂/MeOH used as solvent instead of 1:1THF/MeOH.

Alternate Preparation of X-33:(3-{-4′-[(2,3-dihydro-1H-inden-2-ylamino)-methyl]-3′,5′-difluoro-3-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl2,2-dimethylpropanoate

A mixture of[3-(3′,5′-difluoro-4′-formyl-3-biphenylyl)-1H-1,2,4-triazol-1-yl]methyl2,2-dimethylpropanoate (67.6 g; 0.17 mol; I-X-9), 2-aminoindane (22.9 g;0.17 mol; freebase obtained commercially) and HOAc (0.48 mL; 0.0085 mol,Note 1) in PhH (350 mL) was heated under reflux using a Dean-Stark trapto remove water. After 1.5 h, volatiles were removed in vacuo, theresidue was dissolved in CH₂Cl₂/HOAc (400:25 mL respectively), andNaBH(OAc)₃ (43 g; 0.203 mol) was added at room temperature. The mixturewas stirred 12 h, and quenched by dropwise addition of water (250 mL).The mixture was stirred 30 min and separated into layers. The organiclayer was washed (satd NaHCO₃, brine), filtered through a pad of Na₂SO₄and concentrated in vacuo. The residue was triturated with MeOH (250mL), the resulting slurry was diluted with water (250 mL) and stirred 30min at room temperature. Solids were collected by filtration, and washedwith water. The cake was air-dried overnight on the filter, affordingthe title compound as an off-white solid, used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.1 (s, 9H), 2.74 (dd,J=15.7, 6.1 Hz, 2H), 3.09 (dd, J=15.8, 7.1 Hz, 2H), 3.54 (quint, J=6.6Hz, 1H), 3.86 (s, 2H), 6.21 (s, 2H), 7.07-7.13 (m, 2H), 7.15-7.21 (m,2H), 7.43-7.52 (m, 2H), 7.60 (t, J=7.7 Hz, 1H), 7.81 (ddd, J=7.9, 1.8,1.1 Hz, 1H), 8.06 (ddd, J=7.8, 1.3, 1.2 Hz, 1H), 8.26 (t, J=1.7 Hz, 1H),8.82 (s, 1H).

-   Note 1 TsOH.H₂O (0.05 equiv) has also been used to catalyse imine    formation between I-X-9 and compounds of Formula III as described    above, with equivalent efficacy.

General Method 1 for Preparation of Compounds of Formula I Example 13′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-4-biphenylcarboxamideHydrochloride

A mixture of 3′-[(2-chloroethyl)oxy]-4-biphenylcarboxamide and3′-[(2-bromoethyl)oxy]-4-biphenylcarboxamide (Example II-1) (0.15 g),4,4-dimethylcyclohexylamine hydrochloride (0.13 g, 0.8 mmol) (preparedaccording to J. Med. Chem. 1971, 14, p. 600-614) and triethylamine (0.14g, 1.35 mmol) in methanol (2 mL) was placed in a microwave at 160° C.until the reaction was complete as monitored by LC/MS. The reactionmixture was poured into ethyl acetate and washed several times with 5%Na₂CO₃ (aq). Silica gel was added to the organic phase and the mixturewas concentrated in vacuo. The residue was purified by silica gelchromatography. The fractions containing the desired product werecombined and concentrated in vacuo. Dissolved the residue in ethanol,added 1.0N HCl in Et₂O until acidic, added ethyl ether until turbid andlet stand at room temperature. The resulting solid was filtered, washedwith ethyl ether and dried to give3′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-4-biphenylcarboxamidehydrochloride as an off-white solid. (M+H) 367, 1.83 min. (LC/MS methodA)

The following examples were prepared from the appropriate halide ofFormula II and the corresponding amine of Formula III according to theprocedure described for Example 1 of General Method 1, with anysignificant deviations being noted below the table.

TABLE 1 Compounds of Formula I Generated from Compounds of Formula IIEx. Structure and Name Characterization Data Method/Comments 2

(M + H) 408, t_(R) 1.43 min. (LC/MS method A). Used II-1 mixed halides3′-{[2-(4-cyclohexyl-1-piperazinyl) ethyl]oxy}-4-biphenylcarboxamidedihydrochloride 3

(M + H) 353, t_(R) 1.64 min. (LC/MS method A). Used II-1 mixed halides3′-{[2-(cycloheptylamino)ethyl]oxy}-4- biphenylcarboxamide hydrochloride4

(M + H) 395, t_(R) 2.02 min. (LC/MS method A). Used II-1 mixed halides3′-[(2-{[4-(1,1-dimethylethyl)cyclo- hexyl]amino}ethyl)oxy]-4-biphenyl-carboxamide hydrochloride 5

(M + H) 341, t_(R) 1.70 min. (LC/MS method A). Used II-1 mixed halides3′-{[2-(hexylamino)ethyl]oxy}-4- biphenylcarboxamide hydrochloride 6

(M + H) 367, t_(R) 1.75 min. (LC/MS method A). Used II-1 mixed halidesand III-3 amine 3′-({2-[(3,3-dimethylcyclohexyl)amino]ethyl}oxy)-4-biphenyl- carboxamide 7

(M + H) 341, t_(R) 1.72 min. (LC/MS method A). Used II-1 mixed halidesand III-6 amine 3′-({2-[(4-methylpentyl)amino]ethyl}oxy)-4-biphenylcarboxamide hydrochloride 8

(M + H) 395, t_(R) 1.98 min. (LC/MS method A). Used II-1 mixed halidesand III-5 amine 3′-({2-[(3,3,5,5-tetramethylcyclo-hexyl)amino]ethyl}oxy)-4-biphenyl- carboxamide hydrochloride 9

(M + H) 367, t_(R) 1.75 min. (LC/MS method A). Used II-1 mixed halides3′-{[2-(cyclooctylamino)ethyl]oxy}-4- biphenylcarboxamide hydrochloride10

(M + H) 367, t_(R) 1.80 min. (LC/MS method B). Used II-1 mixed halides3′-({2-[(cycloheptylmethyl)amino] ethyl}oxy)-4- biphenylcarboxamidehydrochloride 11

(M + H) 327, t_(R) 1.57 min. (LC/MS method A) Used II-1 mixed halides¹⁾3′-({2-[(3-methylbutyl)amino] ethyl}oxy)-4-biphenylcarboxamidetrifluoroacetate 12

(M + H) 313, t_(R) 1.40 min. (LC/MS method A). Used II-1 mixed halides¹⁾3′-({2-[(2-methylpropyl)amino] ethyl}oxy)-4-biphenylcarboxamidetrifluoroacetate 13

(M + H) 365, t_(R) 1.60 min. (LC/MS method A). Used II-1 mixed halides¹⁾3′-[(2-{[(3-fluorophenyl)methyl] amino}ethyl)oxy]-4-biphenyl-carboxamide trifluoroacetate 14

(M + H) 353, t_(R) 1.69 min. (LC/MS method A). Used II-1 mixed halides¹⁾3′-({2-[(cyclohexylmethyl)amino] ethyl}oxy)-4-biphenylcarboxamidetrifluoroacetate 15

(M + H) 379, t_(R) 1.62 min. (LC/MS method A). Used II-1 mixed halides¹⁾3′-[(2-{[2-(3-fluorophenyl)ethyl] amino}ethyl)oxy]-4-biphenyl-carboxamide trifluroroacetate 16

(M + H) 367, t_(R) 1.55 min. (LC/MS method A). Used II-1 mixedhalides^(1,2)) 3′-[(2-{[2-(2-thienyl)ethyl] amino}ethyl)oxy]-4-biphenyl-carboxamide 17

(M + H) 381, t_(R) 1.90 min. (LC/MS method A) Used II-2 chloride andIII-1 amine 3′-[(2-{[(4,4-dimethylcyclohexyl) methyl]amino}ethyl)oxy]-4-biphenylcarboxamide hydrochloride 18

(M + H) 373, t_(R) 1.66 min. (LC/MS method B). Used II-2 chloride3′-{[2-(2,3-dihydro-1H-inden-2- ylamino)ethyl]oxy}-4-biphenyl-carboxamide hydrochloride 19

(M + H) 367, t_(R) 1.77 min. (LC/MS method A) Used II-3 mixed halidesand III-1 amine 4′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-3-biphenylcarboxamide hydrochloride 20

(M + H) 353, t_(R) 1.65 min. (LC/MS method A). Used II-3 mixed halides4′-{[2-(cycloheptylamino)ethyl]oxy}-3- biphenylcarboxamide hydrochloride21

(M + H) 367, t_(R) 1.75 min. (LC/MS method A). Used II-3 mixed halidesand III-3 amine²⁾ Reaction time 6 hr (1.5 hr at 160° C. and 4.5 hr at150° C.) 4′-({2-[(3,3-dimethylcyclohexyl) amino]ethyl}oxy)-3-biphenyl-carboxamide 22

(M + H) 341, t_(R) 1.71 min. (LC/MS method A). Used II-3 mixed halides²⁾4′-({2-[(4-methylpentyl)amino] ethyl}oxy)-3-biphenylcarboxamide 23

(M + H) 395, t_(R) 2.03 min. (LC/MS method A). Used II-3 mixed halidesand III-5 amine Used CH₃CN/ethyl ether to form HCl salt4′-({2-[(3,3,5,5-tetramethylcyclo- hexyl)amino]ethyl}oxy)-3-biphenyl-carboxamide hydrochloride 24

(M + H) 353, t_(R) 1.66 min (LC/MS method A) Used II-3 mixed halides¹⁾4′-({2-[(cyclohexylmethyl) amino]ethyl}oxy)-3-biphenyl- carboxamidetrifluoroacetate 25

(M + H) 367, t_(R) 1.82 min. (LC/MS method B). Used II-3 mixed halides4′-({2-[(cycloheptylmethyl)amino] ethyl}oxy)-3-biphenylcarboxamidehydrochloride 26

(M + H) 327, t_(R) 1.52 min. (LC/MS method A). Used II-3 mixed halides¹⁾4′-({2-[(3-methylbutyl)amino]ethyl} oxy)-3-biphenylcarboxamidetrifluoroacetate 27

(M + H) 379, t_(R) 1.64 min. (LC/MS method A). Used II-3 mixed halides¹⁾4′-[(2-{[2-(3-fluorophenyl)ethyl] amino}ethyl)oxy]-3-biphenyl-carboxamide trifluoroacetate 28

(LC/MS Method A) t_(R) 1.59 min, m/z 361 (M + H, freebase) Used II-4chloride^(1,3)): 30 min NaI 4′-({2-[(2- phenylethyl)amino]ethyl}oxy)-3-biphenylcarboxamide trifluoroacetate 29

(LC/MS Method A) t_(R) 1.63 min, m/z 375 (M + H, freebase) Used II-4chloride^(1,3)): 90 min, Bu₄NI used in lieu of NaI 4′-({2-[methyl(2-phenylethyl)amino]ethyl}oxy)-3- biphenylcarboxamide trifluoroacetate 30

(LC/MS Method A) t_(R) 1.51 min, m/z 347 (M + H, freebase) Used II-4chloride^(1,3,4)): 45 min NaI 4′-({2- [(Phenylmethyl)amino]ethyl}oxy)-3-biphenylcarboxamide trifluoroacetate 31

(LC/MS Method A) t_(R) 1.66 min, m/z 361 (M + H, freebase) Used II-4chloride^(1,3,4)): 45 min NaI 4′-[(2-{[(4- methylphenyl)methyl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 32

(LC/MS Method A) t_(R) 1.70 min, m/z 381 (M + H, freebase) Used II-4chloride^(1,3,4)): 45 min NaI 4′-[(2-{[(4-chlorophenyl)methyl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 33

(LC/MS Method A) t_(R) 1.53 min, m/z 361 (M + H, freebase) Used II-4chloride^(1,3,4)): 45 min NaI 4′-({2- [methyl(phenylmethyl)amino]ethyl}oxy)-3-biphenylcarboxamide trifluoroacetate 34

(LC/MS Method A) t_(R) 1.56 min, m/z 365 (M + H, freebase) Used II-4chloride^(3,4)): 30 min NaI 4′-[(2-{[(3-fluorophenyl)methyl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 35

(LC/MS Method A) t_(R) 1.59 min, m/z 383 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[(3,5-difluorophenyl)methyl]amino} ethyl)oxy]-3-biphenylcarboxamidetrifluoroacetate 36

(LC/MS Method A) t_(R) 1.88 min, m/z 423 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[(diphenylmethyl)amino]ethyl}oxy)-3-biphenyl- carboxamide trifluoroacetate 37

(LC/MS Method A) t_(R) 1.20 min, m/z 329 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{methyl[2-(methyloxy)ethyl]amino}ethyl)oxy]-3-biphenyl- carboxamide trifluoroacetate 38

(LC/MS Method A) t_(R) 1.65 min, m/z 373 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-{[2-(2,3-dihydro-1H-inden-2-ylamino)ethyl]oxy}-3- biphenylcarboxamide trifluoroacetate 39

(LC/MS Method A) t_(R) 1.55 min, m/z 341 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[methyl(3-methylbutyl)amino]ethyl}oxy)-3-biphenylcarboxamide trifluoroacetate 40

(LC/MS Method A) t_(R) 1.53 min, m/z 353 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[cyclohexyl(methyl)amino]ethyl}oxy)-3-biphenylcarboxamide trifluoroacetate 41

(LC/MS Method A) t_(R) 0.24 min, m/z 356 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[4-(dimethylamino)butyl]amino}ethyl)oxy]-3-biphenylcarboxamide bis(trifluoroacetate) 42

(LC/MS Method A) t_(R) 1.67 min, m/z 375 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI rac 4′-({2-[(2-phenylpropyl)amino]ethyl}oxy)-3-biphenyl- carboxamide trifluoroacetate 43

(LC/MS Method A) t_(R) 1.37 min, m/z 343 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[3-(methyloxy)propyl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 44

(LC/MS Method A) t_(R) 1.04 min, m/z 327 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-{[2-(4-morpholinyl)ethyl]oxy}-3-biphenylcarboxamide trifluoroacetate 45

(LC/MS Method A) t_(R) 1.54 min, m/z 373 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-{[2-(3,4-dihydro-2(1H)-isoquinolinyl)ethyl]oxy}-3- biphenylcarboxamide trifluoroacetate 46

(LC/MS Method A) t_(R) 0.73 min, m/z 342 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[[2- (dimethylamino)ethyl](methyl)amino]ethyl}oxy)-3- biphenylcarboxamide bis(trifluoroacetate) 47

(LC/MS Method A) t_(R) 1.45 min, m/z 353 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[(2-thienylmethyl)amino]ethyl}oxy)-3- biphenylcarboxamide trifluoroacetate48

(LC/MS Method A) t_(R) 1.47 min, m/z 412 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI ethyl 4-[(2-{[3′-(aminocarbonyl)-4-biphenylyl]oxy}ethyl)amino]-1- piperidinecarboxylate trifluoroacetate 49

(LC/MS Method A) t_(R) 1.36 min, m/z 313 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[(2-methylpropyl)amino]ethyl}oxy)-3- biphenylcarboxamide trifluoroacetate 50

(LC/MS Method A) t_(R) 0.83 min, m/z 362 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[2-(3-pyridinyl)ethyl]amino}ethyl)oxy]-3- biphenylcarboxamidebis(trifluoroacetate) 51

(LC/MS Method A) t_(R) 1.14 min, m/z 315 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[2-(methyloxy)ethyl]amino}ethyl)oxy]-3- biphenylcarboxamidetrifluoroacetate 52

(LC/MS Method A) t_(R) 1.24 min, m/z 329 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[3-(methyloxy)propyl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 53

(LC/MS Method A) t_(R) 1.66 min, m/z 373 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI rac 4′-{[2-(2,3-dihydro-1H-inden-1-ylamino)ethyl]oxy}-3- biphenylcarboxamide trifluoroacetate 54

(LC/MS Method A) t_(R) 0.85 min, m/z 370 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[2-(4-morpholinyl)ethyl]amino}ethyl)oxy]-3- biphenylcarboxamidebis(trifluoroacetate) 55

(LC/MS Method B) t_(R) 1.90 min, m/z 381 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI rac 4′-({2-[(3,3,5-trimethylcyclohexyl)amino]ethyl}oxy)-3- biphenylcarboxamide trifluoroacetate 56

(LC/MS Method B) t_(R) 1.61 min, m/z 351 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[(1R,3r,5S)-bicyclo[3.1.1]hept-3-ylamino]ethyl}oxy)-3- biphenylcarboxamide trifluoroacetate 57

(LC/MS Method B) t_(R) 1.93 min, m/z 393 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 58

(LC/MS Method B) t_(R) 1.93 min, m/z 393 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3- yl]amino}ethyl)oxy]-3-biphenylcarboxamide trifluoroacetate 59

(LC/MS Method B) t_(R) 1.77 min, m/z 391 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-{[2-(tricyclo[3.3.1.1^(3,7)]dec-1-ylamino)ethyl]oxy}-3- biphenylcarboxamide trifluoroacetate 60

(LC/MS Method B) t_(R) 2.82 min, m/z 365 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-({2-[(3-fluorophenyl)(methyl)amino]ethyl}oxy)-3-biphenylcarboxamide trifluoroacetate 61

(LC/MS Method B) t_(R) 2.78 min, m/z 359 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-{[2-(2,3-dihydro-1H-indo1-1-yl)ethyl]oxy}-3-biphenylcarboxamide trifluoroacetate 62

(LC/MS Method B) t_(R) 1.66 min, m/z 377 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI 4′-[(2-{[2-(phenyloxy)ethyl]amino}ethyl)oxy]-3- biphenylcarboxamidetrifluoroacetate 63

(LC/MS Method B) t_(R) 1.34 min, m/z 365 (M + H, freebase) Used II-4chloride^(1,3,4)): 30 min NaI methyl N-(2-{[3′-(aminocarbonyl)-4-biphenylyl]oxy}ethyl)glycinate trifluoroacetate 64

(M + H) 327, t_(R) 1.61 min. (LC/MS Method A) Used II-5 mixed halide3′-({2-[(3- methylbutyl)amino]ethyl}oxy)-3- biphenylcarboxamidehydrochloride 65

(M + H) 353, t_(R) 1.76 min. (LC/MS Method A). Used II-5 mixed halide3′-({2-[(cyclohexylmethyl)amino] ethyl}oxy)-3-biphenylcarboxamidehydrochloride 66

(M + H) 379, t_(R) 1.70 min. (LC/MS Method A). Used II-5 mixed halide3′-[(2-{[2-(3-fluorophenyl)ethyl] amino}ethyl)oxy]-3-biphenyl-carboxamide hydrochloride 67

(M + H) 367, t_(R) 2.42 min. (LC/MS method A) Used II-6 mixed halideIsolated from the reaction mixture using trituration with Et₂O and thenproceeded as before to form the HCl salt 4′-[(2-{[2-(2-thienyl)ethyl]amino}ethyl)oxy]-4- biphenylcarboxamide Hydrochloride 68

(M + H) 353, t_(R) 1.92 min. (LC/MS method A). Used II-6 mixed halideIsolated from the reaction mixture using trituration with Et₂O and thenproceeded as before to form the HCl salt 4′-({2-[(cyclohexylmethyl)amino] ethyl}oxy)-4-biphenylcarboxamide hydrochloride 69

(M + H) 379, t_(R) 2.48 min. (LC/MS method A). Used II-6 mixed halideIsolated from the reaction mixture using trituration with Et₂O and thenproceeded as before to form the HCl salt4′-[(2-{[2-(3-fluorophenyl)ethyl] amino}ethyl)oxy]-4-biphenyl-carboxamide hydrochloride 70

(M + H) 327, t_(R) 1.78 min. (LC/MS method A). Used II-6 mixed halideIsolated from the reaction mixture using trituration with Et₂O and thenproceeded as before to form the HCl salt4′-({2-[(3-methylbutyl)amino]ethyl} oxy)-4-biphenylcarboxamidehydrochloride 71

(M + H) 365, t_(R) 2.20 min. (LC/MS method A). Used II-6 mixed halideIsolated from the reaction mixture using trituration with Et₂O and thenproceeded as before to form the HCl salt4′-[(2-{[(3-fluorophenyl)methyl] amino}ethyl)oxy-4-biphenyl- carboxamidehydrochloride 72

(M + H) 367, t_(R) 1.73 min. (LC/MS Method A) Used II-7 mixed halide3′-{[2-(cycloheptylamino)ethyl]oxy}-2- methyl-4-biphenylcarboxamidehydrochloride 73

(M + H) 341, t_(R) 1.63 min. (LC/MS Method A). Used II-7 mixed halide2-methyl-3′-({2-[(3-methylbutyl) amino]ethyl}oxy)-4-biphenyl-carboxamide hydrochloride 74

(M + H) 367, t_(R) 1.84 min. (LC/MS Method A). Used II-7 mixed halide3′-({2-[(cyclohexylmethyl)amino] ethyl}oxy)-2-methyl-4-biphenyl-carboxamide hydrochloride 75

(M + H) 395, t_(R) 2.03 min. (LC/MS Method B) Used II-8 chloride3′-[(2-{[(4,4- dimethylcyclohexyl)methyl]amino} ethyl)oxy]-2-methyl-4-biphenylcarboxamide hydrochloride 76

(M + H) 387, t_(R) 1.78 min. (LC/MS method A Used II-8 chloride Preparedthe HCl salt as before. Converted to free base and purified a secondtime using reverse phase chromatography. Triturated with dichloromethaneas a final purification. 3′-{[2-(2,3-dihydro-1H-inden-2-ylamino)ethyl]oxy}-2-methyl-4- biphenylcarboxamide trifluoroacetate 77

(M + H) 371, t_(R) 1.74 min. (LC/MS Method A) Used II-9 mixed halide3′-({2- [(cyclohexylmethyl)amino]ethyl}oxy)-2-fluoro-4-biphenylcarboxamide hydrochloride 78

(M + H) 345, t_(R) 1.63 min. (LC/MS Method A). Used II-9 mixed halide2-fluoro-3′-({2-[(3-methylbutyl) amino]ethyl}oxy)-4-biphenyl-carboxamide hydrochloride 79

(M + H) 397, t_(R) 1.69 min. (LC/MS Method A). Used II-9 mixed halide2-fluoro-3′-[(2-{[2-(3-fluorophenyl) ethyl]amino}ethyl)oxy]-4-biphenyl-carboxamide hydrochloride 80

(M + H) 345, t_(R) 1.58 min. (LC/MS Method A) Used II-10 mixed halide2′-fluoro-5′-({2-[(3-methyl- butyl)amino]ethyl}oxy)-4-biphenylcarboxamide hydrochloride 81

(M + H) 371, t_(R) 1.72 min. (LC/MS Method A). Used II-10 mixed halide5′-({2-[(cyclohexylmethyl)amino] ethyl}oxy)-2′-fluoro-4-biphenyl-carboxamide hydrochloride 82

(M + H) 397, t_(R) 1.68 min. (LC/MS Method A). Used II-10 mixed halide2′-fluoro-5′-[(2-{[2-(3-fluorophenyl) ethyl]amino}ethyl)oxy]-4-biphenyl-carboxamide hydrochloride 83

(M + H) 341, t_(R) 1.68 min. (LC/MS Method A) Used II-11 mixed halide3′-({3-[(3-methylbutyl)amino]propyl} oxy)-4-biphenylcarboxamidehydrochloride 84

(M + H) 328, t_(R) 1.43 min (LC/MS Method A) Used II-12 chlorideisolated by filtration 6-(3-{[2- (Pentylamino)ethyl]oxy}phenyl)-3-pyridinecarboxamide Hydrochloride 85

(M + H) 418, t_(R) 1.43 min (LC/MS method A) Used II-12 chlorideIsolated by filtration and then free-based using N,N-diisopropylethylamine. 6-(3-{[2-(4-hydroxy-4-phenyl-1-piperidinyl)ethyl]oxy}phenyl)-3- pyridine carboxamide 86

¹H NMR (400 MHz, DMSO- d₆) δ ppm 0.85 (s, 6H) 1.20 (m, 2H) 1.39-1.60 (m,4H) 1.83 (m, 2H) 3.02 (m, 1H) 3.39 (br., 2H) 4.30 (m, 2H) 7.10 (d, 2H)7.62 (s, 1H) 7.79 (d, 2H) 8.22 (s, 1H) 8.41 (s, 1H) 8.60 (br., 2H) 8.95(s, 1H) 8.99 (s, 1H); (M + H) 368, 1.55 min (LC/MS method A) Used II-13chloride and III-1 amine¹⁾ 5-[4-({2-[(4,4- Dimethylcyclohexyl)amino]-ethyl}oxy)phenyl]-3- pyridinecarboxamide Trifluoroacetate 87

(M + H) 328, t_(R) 1.28 min (LC/MS method A) Used II-13 chlorideIsolated by filtration from the reaction 5-[4-({2-[(3-methylbutyl)amino]ethyl}oxy)phenyl]- 3-pyridinecarboxamide hydrochloride88

(M + H) 355, t_(R) 1.41 min (LC/MS Method A) Used II-13 chloride5-[4-({2- [(cyclohexylmethyl)amino]ethyl}oxy)phenyl]-3-pyridinecarboxamide 89

(M + H) 381, t_(R) 1.37 min (LC/MS Method A) Used II-13 chloride5-{4-[(2-{[2-(3- fluorophenyl)ethyl]amino}ethyl)oxy]phenyl}-3-pyridinecarboxamide 90

(M + H) 355, t_(R) 1.37 min (LC/MS method A) Used II-13 chlorideIsolated by filtration from the reaction 5-(4-{[2-(cycloheptylamino)ethyl]oxy}phenyl)- 3-pyridinecarboxamide 91

(M + H) 368, t_(R) 1.23 min (LC/MS method A) Used II-13 chlorideIsolated by filtration from the reaction 5-{4-[(2-{[2-(2-thienyl)ethyl]amino}ethyl)oxy]phenyl}- 3-pyridinecarboxamidehydrochloride 92

(M + H) 366, t_(R) 1.57 min (LC/MS Method A) Used II-13 chloride¹⁾5-{4-[(2-{[2-(1-cyclohexen-1- yl)ethyl]amino}ethyl)oxy]phenyl}-3-pyridinecarboxamide trifluoroacetate 93

(M + H) 392, t_(R) 1.50 min (LC/MS Method A) Used II-13 chloride5-[4-({2-1(1S,3s)tricycle [3.3.1.1^(3,7)]dec-1-ylamino]ethyl}oxy)phenyl]-3- pyridinecarboxamide 94

(M + H) 370, t_(R) 0.75 min (LC/MS Method A) Used II-13 chloride5-[4-({2-[4-(2-hydroxyethyl)-1- pipendinyl]ethyl}oxy)phenyl]-3-pyridinecarboxamide 95

(M + H) 356, t_(R) 0.64 min (LC/MS Method A) Used II-13 chloride5-[4-({2-[4-(hydroxymethyl)-1- piperidinyl]ethyl}oxy)phenyl]-3- pyridinecarboxamide 96

(M + H) 416, t_(R) 1.57 min (LC/MS method A) Used II-13 chlorideIsolated and submitted as the free-base after chromatography step5-[4-({2-[4-(phenylmethyl)-1- piperidinyl]ethyl}oxy)phenyl]-3- pyridinecarboxamide 97

(M + H) 418, t_(R) 1.25 min (LC/MS method A) Used II-13 chlorideIsolated by filtration from the reaction 5-(4-{[2-(4-hydroxy-4-phenyl-1-piperidinyl)ethyl]oxy}phenyl)-3- pyridinecarboxamide 98

(M + H) 359, t_(R) 1.61 min (LC/MS Method A) Used II-14 chloride¹⁾5-(4-{[2-(Cycloheptylamino)ethyl]oxy}- phenyl)-2-thiophenecarboxamideTrifluoroacetate 99

(M + H) 332, t_(R) 1.50 min (LC/MS Method A) Used II-15 chloride¹⁾5-[3-({2-[(3- Methylbutyl)amino]ethyl}oxy)phenyl]-2-thiophenecarboxamide trifluoroacetic acid salt 100

(M + H) 358, t_(R) 1.65 min (LC/MS Method A) Used II-15 chloride¹⁾5-[3-({2- [(cyclohexylmethyl)amino]ethyl}oxy)phenyl]-2-thiophenecarboxamide trifluoroacetic acid salt 101

(M+) 372, t_(R) 1.73 min (LC/MS Method A) Used II-15 chloride and III-1amine^(1,2)) 5-[3-({2-[(4,4- dimethylcyclohexyl)amino]ethyl}oxy)phenyl]-2-thiophenecarboxamide trifluoroacetic acid salt 102

(M + H) 333, t_(R) 1.51 min (LC/MS Method A) Used II-15 chloride¹⁾5-[4-({2-[(3- methylbutyl)amino]ethyl}oxy)phenyl]-2-thiophenecarboxamide trifluoroacetic acid salt 103

(M + H) 359, t_(R) 1.68 min (LC/MS Method A) Used II-15 chloride¹⁾5-[4-({2- [(cyclohexylmethyl)amino]ethyl}oxy)phenyl]-2-thiophenecarboxamide trifluoroacetic acid salt 104

(M + H) 373, t_(R) 1.74 min (LC/MS Method A) Used II-15 chloride andIII-1 amine¹⁾ 5-[4-({2-[(4,4- dimethylcyclohexyl)amino]ethyl}oxy)phenyl]-2-thiophenecarboxamide trifluoroacetic acid salt 105

(M + H) 372, t_(R) 1.79 min (LC/MS Method A) Used II-15 chloride andIII-7¹⁾ 5-[4-({2-[(2- cyclohexylethyl)amino]ethyl}oxy)phen-yl]-2-thiophenecarboxamide trifluoroacetic acid salt 106

(M + H) 344, t_(R) 1.47 min (LC/MS Method A) Used II-15 chloride¹⁾5-(4-{[2- (cyclohexylamino)ethyl]oxy}phenyl)-2- thiophenecarboxamidetrifluoroacetic acid salt 107

(M + H) 335, t_(R) 1.51 min (LC/MS Method A) Used II-16 chloride2-[3-({2-[(3- Methylbutyl)amino]ethyl}oxy)-phenyl]-1,3-thiazole-4-carboxamide 108

(M + H) 386, t_(R) 1.63 min (LC/MS Method A) Used II-16 chloride2-{3-[(2-{[2-(3-fluorophenyl) ethyl]amino}ethyl)oxy]phenyl}-1,3-thiazole-4-carboxamide 109

(M + H) 374, t_(R) 1.80 min (LC/MS Method A) Used II-17 chloride andIII-1 amine 2-[4-({2-[(4,4- Dimethylcyclohexyl)amino]-ethyl}oxy)phenyl]-1,3-thiazole-4- carboxamide 110

(M + H) 334, t_(R) 1.39 min (LC/MS Method A) Used II-17 chloride2-[4-({2-[(3-methylbutyl) amino]ethyl}oxy)phenyl]-1,3-thiazole-4-carboxamide hydrochloride 111

(M + H) 360, t_(R) 1.54 min (LC/MS Method A) Used II-17 chloride2-[4-({2-[(cyclohexylmethyl) amino]ethyl}oxy)phenyl]-1,3-thiazole-4-carboxamide Note 1: In some cases, final compounds prepared by thismethod required purification. These compounds were purified by RP-HPLC(C₁₈ column, MeCN/H₂O gradient with TFA additive), yielding finalcompounds (as TFA salts). Note 2: Free-based the resulting salt. Note 3:Sometimes a promoter such as NaI, Bu₄NI was used to facilitate thereaction. Note 4: Reaction performed by microwave heating (90-100° C.,220 W, with air-cooling) in a septum-sealed tube for 30 min intervalsuntil starting material consumed.

General Method 2 for Preparation of Compounds of Formula I Example 1124-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-thienyl]benzamide

To a 5 ml conical vial was added[(5-bromo-2-thienyl)methyl][2-(3-fluorophenyl)ethyl]amine (210 mg, 0.67mmol, Intermediate V-1), (4-aminocarbonylphenyl) boronic acid (110 mg,0.67 mmol), PdCl₂(PPh₃)₂ (49 mg, 0.07 mmol), K₃PO₄ (426 mg, 2.0 mmol)and DME/H₂O (3/1, 4 mL). The reaction mixture was placed in a microwaveat 100° C. for 30 min. The mixture was filtered through a plug of silicagel and purified by RP-HPLC (C₁₈ column, MeCN/H₂O gradient with TFAadditive) to yield 23 mg of4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-thienyl]benzamidetrifluoroacetate. (M+H) 355, 1.43 min (LC/MS method A).

TABLE 2 Compounds of Formula I from Compounds of Formula V Ex. Structureand Name Characterization Data Method/Comments 113

(M + H) 343, 1.14 min (LC/MS method A) Used Intermediate V-2 and 4-bromobenzamide 4-[5-({[2-(2-thienyl)ethyl]amino}methyl)-2-thienyl]benzamide trifluoroacetate 114

(M + H) 303, 1.36 min (LC/MS method A) Used Intermediate V-3 and 4-bromobenzamide 4-(5-{[(3-methylbutyl)amino]methyl}-2- thienyl)benzamidetrifluoroacetate 115

(M + H) 303, 1.32 min (LC/MS method A) Used Intermediate V-4 and 4-bromobenzamide 4-(5-{[(3-methylbutyl)amino]methyl}-3- thienyl)benzamidetrifluoroacetate 116

(M + 1) 343, 1.55 min (LC/MS method A) Used Intermediate V-5 and 4-bromobenzamide 4-[5-({[2-(2-thienyl)ethyl]amino}methyl)-3-thienyl]benzamide trifluoroacetate 117

(M + 1) 355, 1.44 min (LC/MS method A) Used Intermediate V-6 and 4-bromobenzamide 4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-3-thienyl]benzamide trifluoroacetate 118

(M + 1) 343, 1.58 min (LC/MS method A) Used Intermediate V-7 and 4-bromobenzamide 4-(5-{[(4,4-dimethylcyclohexyl)amino]methyl}-3-thienyl)benzamide trifluoroacetate 119

(M + 1) 343, 1.61 min (LC/MS method A) Used Intermediate V-7 and IV-63-(5-{[(4,4-dimethylcyclohexyl) amino]methyl}-3-thienyl)benzamidetrifluoroacetate 120

(LC/MS Method A) 1.76 min, m/z 351 (M + H, freebase) Used IntermediateV-9 and [3- (aminocarbonyl) phenyl]boronic acid ¹⁾4′-{(1R)-1-[(4,4-dimethylcyclohexyl) amino]ethyl}-3-biphenylcarboxamidetrifluoroacetate 121

(LC/MS Method A) 1.75 min, m/z 351 (M + 1, freebase) Used IntermediateV-10 and [3- (aminocarbonyl) phenyl]boronic acid ¹⁾4′-{(1S)-1-[(4,4-dimethylcyclohexyl) amino]ethyl}-3-biphenylcarboxamidetrifluoroacetate 122

LC/MS (method A) 1.77 min; m/z 363 (M + H) Used Intermediate V-21 and[3- (aminocarbonyl) phenyl]boronic acid PhMe/EtOH (4:1) as organiccosolvent ^(1,2)) 3-{1-[(4,4-dimethylcyclohexyl)amino]-2,3-dihydro-1H-inden-5-yl}benzamide hydrochloride Note 1: Na₂CO₃ wasused as the base in the coupling in place of K₃PO₄. Note 2: In lieu ofthe HPLC purification step, chromatography on ISCO amine-functionalizedsilica column using Hex/EtOAc eluted the compound. This was furthersubjected to HCl and concentrated to the HCl salt.

General Method 3 for Preparation of Compounds of Formula I Example 123N-[4′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-4-biphenylyl]acetamidetrifluoroacetate

To a solution of 1,1-dimethylethyl(2-{[4′-(acetylamino)-4-biphenylyl]oxy}ethyl)(4,4-dimethylcyclohexyl)carbamate (0.0624 g; 0.13 mmol; IntermediateVI-1) and Et₃SiH (0.060 mL; 0.37 mmol; ≧2.5 equiv) in CH₂Cl₂ (2 mL) atrt was added TFA (1 mL). The mixture was aged 3 h and concentrated todryness, affording the title compound as a colorless solid (see Note 1).(LC/MS Method A) 1.83 min, m/z 381 (M+H, freebase).

-   Note 1) In some cases, final compounds prepared by this method    required purification. These compounds were purified by RP-HPLC (C₁₈    column, MeCN/H₂O gradient with TFA additive), yielding final    compounds (as TFA salts).

TABLE 3 Compounds of Formula I from Compounds of Formula VI Method/ Ex.Structure and Name Characterization Data Comments 124

Note 2 Used Intermediate VI-2 N-[4′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-3-biphenylyl]acetamide trifluoroacetate 125

LC/MS (LC/MS Method A) 1.85 min, m/z 415 (M − H, freebase). UsedIntermediate VI-3 N-[4′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-3- biphenylyl]methanesulfonamidetrifluoroacetate 126

(LC/MS Method A) 1.43 min, m/z 390 (M + H, freebase) Used IntermediateVI-4 N-(2-{[3′-(1H-imidazol-2-yl)-4- biphenylyl]oxy}ethyl)-4,4-dimethylcyclohexanamine trifluoroacetate 127

(LC/MS Method A) 1.41 min, m/z 390 (M + 1, freebase) Used IntermediateVI-5 N-(2-{[4′-(1H-imidazol-2-yl)-4- biphenylyl]oxy}ethyl)-4,4-dimethylcyclohexanamine trifluoroacetate 128

(LC/MS Method A) 1.75 min, m/z 381 (M + 1, freebase) Used IntermediateVI-6 4′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-6-methyl-3-biphenylcarboxamide trifluoroacetate 129

(LC/MS Method A) 1.87 min, m/z 381 (M + 1) Used Intermediate VI-74′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-2-methyl-3-biphenylcarboxamide trifluoroacetate 130

Need Data Used Intermediate VI-8¹⁾4′-{[(4,4-Dimethylcyclohexyl)amino]methyl}-3- biphenylcarboxamidetrifluoroacetate 131

LC/MS (LC/MS Method A) 1.63 min, m/z 337 (M + H, freebase) UsedIntermediate VI-9 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-4-biphenylcarboxamide trifluoroacetate 132

(LC/MS Method A) 1.76 min, m/z 351 (M + H, freebase) Used IntermediateVI-10 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-6-methyl-3-biphenylcarboxamide trifluoroacetate 133

(LC/MS Method A) 1.64 min, m/z 351 (M + H, freebase) Used IntermediateVI-11 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2-methyl-3-biphenylcarboxamide trifluoroacetate 134

(LC/MS Method A) 1.72 min, m/z 351 (M + H, freebase) Used IntermediateVI-12 4′-{2-[(4,4-dimethylcyclohexyl)amino]ethyl}-3- biphenylcarboxamidetrifluoroacetate 135

LC/MS (LC/MS Method A) 0.75 min, m/z 406.3 (M + 1, freebase) UsedIntermediate VI-13, final compound was free-based, then treated with1.0M HCl in Et₂O 1-[4′-({2-[(4,4-dimethylcyclohexyl)amino]ethyl}oxy)-3-biphenylyl]-1,3-dihydro-2H- imidazol-2-onehydrochloride 136

LC/MS (LC/MS Method A) 0.76 min, m/z 443.3 (M + 1, freebase) UsedIntermediate VI-14, final compound was free-based, then treated with1.0M HCl in Et₂O N-(2-{[3′-(1,1-dioxido-2-isothiazolidinyl)-4-biphenylyl]oxy}ethyl)-4,4-dimethyl cyclohexanamine hydrochloride 137

Note 3 Used Intermediate VI-15(4,4-Dimethylcyclohexyl)(2-{[3′-(1,2,4-oxadiazol-3-yl)-4-biphenylyl]oxy}ethyl)amine trifluoroacetate 138

LC/MS (method E) 0.67 min; m/z 427 (M + H) Used Intermediate VI-184′-{[(4,4-dimethylcyclohexyl)amino]methyl}-N-(phenylmethyl)-3-biphenylcarboxamide trifluoroacetate 139

LC/MS (method E) 0.69 min; m/z 441 (M + H) Used Intermediate VI-164′-{[(4,4-dimethylcyclohexyl)amino]methyl}-N-(2-phenylethyl)-3-biphenylcarboxamide trifluoroacetate 140

LC/MS (method E) 0.71 min; m/z 455 (M + H) Used Intermediate VI-174′-{[(4,4-dimethylcyclohexyl)amino]methyl}-N-(3-phenylpropyl)-3-biphenylcarboxamide trifluoroacetate 141

LC/MS (method E) 0.75 min; m/z 517 (M + H) Used Intermediate VI-19N-[2-(4-biphenylyl)ethyl]-4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-3-biphenylcarboxamide trifluoroacetate 142

LC/MS (method B) 1.72 min; m/z 364 (M + H) Used Intermediate VI-20N-{[3′-(1H-imidazol-4-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine trifluoroacetate Note 1: The title compoundwas also prepared as described in General Method X (TFA salt) andGeneral Method Y (HCl salt). Note 2: ¹H NMR (400 MHz, DMSO-d₆) δ 0.91(s, 6H), 1.2 (app. T, J = 12.5 Hz, 2H), 1.43 (app. D, J = 13.1 Hz, 2H),1.55 (app. D, J = 12.2 Hz, 2H), 1.88 (app. D, J = 11.1 Hz, 2H), 2.06 (s,3H), 3.04 (br. s, 1H), 4.27 (br. s, 2H), 7.09 (m, 2H), 7.26 (d, J = 7.2Hz, 1H), 7.34 (app. T, J = 7.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.57(m, 2H), 7.90 (s, 1H), 8.66 (br. s, 1H), 10.03 (s, 1H). (N.B.: missingCH₂ signal assumed to be obscured by water peak). Note 3: ¹H NMR (400MHz, DMSO-d₆) δ 0.91 (s, 6H), 1.22 (app. t, J = 13.0 Hz, 2H), 1.44 (app.d, J = 13.0 Hz, 2H), 1.55 (app. q, J = 12.4 Hz, 2H), 1.88 (app. d, J =11.2 Hz, 2H), 3.04 (m, 1H), 4.29 (unresolved t, 2H), 7.13 (m, 2H), 7.65(app. t, J = 7.8 Hz, 1H), 7.72 (m, 2H), 7.86 (d, J = 7.6 Hz, 1H), 7.99(d, J = 7.5 Hz, 1H), 8.23 (s, 1H), 8.52-8.84 (br. s, 2H), 9.73 (s, 1H)(N.B.: missing CH₂ signal assumed to be obscured by water peak).

General Method 4 for Preparation of Compounds of Formula I Example 1434′-({2-[(4,4-Dimethylcyclohexyl)amino]ethyl}oxy)-2′-methyl-3-biphenylcarboxamidetrifluoroacetate

To a solution of 4′-[(2-aminoethyl)oxy]-2′-methyl-3-biphenylcarboxamidetrifluoroacetate (0.105 g; 0.273 mmol; Intermediate VII-1) and4,4-dimethylcyclohexanone (0.038 g; 0.30 mmol; Intermediate Step 1 ofIII-1) in MeOH/CH₂Cl₂/HOAc (3 mL; 1:1 MeOH/CH₂Cl₂ with 5% HOAc) wasadded Et₃N (0.040 mL; 0.27 mmol), followed by PS-BH₃CN (0.32 g; ca. 4.2mmol/g; ca. 1.35 mmol BH₃CN). The mixture was agitated overnight at rtusing an orbital shaker, and the resin was removed by filtration. Thefiltrate was concentrated in vacuo, and the residue was purified byRP-HPLC (C₁₈ column, MeCN/H₂O gradient with TFA additive) affording thetitle compound as a colorless foam. (LC/MS Method C) 2.24 min, m/z 381(M+1, freebase).

The following were prepared in a manner similar to that described in theabove example with notation and comment provided for the particularexample below the table.

TABLE 4 Compounds of Formula I from Compounds of Formula VII Ex.Structure and Name Characterization Data Method/Comments 144

(M + H) 381, 1.83 min. (LC/MS method A) Used VII-2 and cyclohexanecarboxaldehyde Note 5, 6 3′-{2-[(cyclohexylmethyl)amino]ethyl}-4-biphenylcarboxamide trifluoroacetate 145

(M + H) 311, 1.55 min. (LC/MS method A) Used VII-2 Note 5, 63′-{2-[(3-methylbutyl)amino]ethyl}-4- biphenylcarboxamidetrifluoroacetate 146

(M + H) 351, 1.49 min. (LC/MS method A) Used VII-3 Note 6, 73′-[1-(3-methylbutyl)-4-piperidinyl]-4- biphenylcarboxamidehydrochloride147

LC/MS (method A) 2.02 min; m/z 363 (M + H). Used I-VII-9 (Boc'd) Note 3and Ex III-1 Step 1 intermed. Note 23-[2-(4,4-dimethylcyclohexyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]benzamide hydrochloride 148

LC/MS (method C) 1.87 min, m/z 323 (M + H). Used VII-43-[2-(3-methylbutyl)-1,2,3,4-tetrahydro-6- isoquinolinyl]benzamidetrifluoroacetate 149

LC/MS (method D) 1.93 min, m/z 363 (M + H). (Used I-VII-10 and Ex III-1Step 1 intermed. Note 3 4-[2-(4,4-dimethylcyclohexyl)-1,2,3,4-tetrahydro-7-isoquinolinyl]benzamide trifluoroacetate 150

LC/MS (method A) 1.8 min; m/z 335 (M + H) Used VII-4 Note 43-(2-cyclohexyl-1,2,3,4-tetrahydro-6- isoquinolinyl)benzamidetrifluoroacetate 151

LC/MS (method A) 2 min; m/z 363 (M + H) Used VII-4 Note 43-[2-(3,3-dimethylcyclohexyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]benzamide trifluoroacetate 152

LC/MS (method A) 1.95 min; m/z 349 (M + H) Used VII-4 Note 43-[2-(cyclohexylmethyl)-1,2,3,4-tetrahydro- 6-isoquinolinyl]benzamidetrifluoroacetate 153

LC/MS (method A) 1.85 min; m/z 343 (M + H) Used VII-4 Purified by flashchromatography, added HCl (4M in dioxane) to column fractions. Note 43-[2-(phenylmethyl)-1,2,3,4-tetrahydro-6- isoquinolinyl]benzamidehydrochloride 154

LC/MS (method A) 1.91 min; m/z 357 (M + H) Used VII-4 Note 43-[2-(2-phenylethyl)-1,2,3,4-tetrahydro-6- isoquinolinyl]benzamidetrifluoroacetate 155

LC/MS (method A) 2.19 min; m/z 363 (M + H) Used VII-5 and Ex III- 1 Step1 Intermed. Note 4 3-{2-[(4,4-dimethylcyclohexyl)amino]-2,3-dihydro-1H-inden-5-yl}benzamide trifluoroacetate 156

LC/MS (method A) 2.06 min; m/z 377 (M + H) Used I-VII-5 and Ex III-1Step 1 intermed. Note 3, 4 3- [2-(4,4-dimethylcyclohexyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]-2- methylbenzamide trifluoroacetate 157

LC/MS (method A) 2.06 min; m/z 382 (M + H) Used I-VII-6 and Ex III-1Step 1 intermed. Note 3, 4 3-[2-(4,4-dimethylcyclohexyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]-2- fluorobenzamide trifluoroacetate 158

LC/MS (method A) 1.79 min; m/z 386 (M + H) Used I-VII-7 and Ex III-1Step 1 intermed. Note 3, 4 2-(4,4-dimethylcyclohexyl)-6-[3-(1H-imidazol-2-yl)phenyl]-1,2,3,4- tetrahydroisoquinoline trifluoroacetate159

LC/MS (method E) 0.52 min; m/z 331 (M + H) Used VII-7 Note 4, 84′-{2-[(phenylmethyl)amino]ethyl}-3- biphenylcarboxamide 160

LC/MS (method E) 0.57 min; m/z 399 (M + H) Used VII-7 Note 4, 84′-[2-({[3-(trifluoromethyl)phenyl]methyl}amino)ethyl]-3-biphenylcarboxamide 161

LC/MS (method E) 0.57 min; m/z 399 (M + H) Used VII-7 Note 4, 84′-[2-({[4-(trifluoromethyl)phenyl]methyl}amino)ethyl]-3-biphenylcarboxamide 162

LC/MS (method E) 0.53 min; m/z 349 (M + H) Used VII-7 Note 4, 7 (priorto HCl salt formation, the freebase was chromatographed on silica usingEtOAc/MeOH) 4′-(2-{[(4-fluorophenyl)methyl]amino}ethyl)-3-biphenylcarboxamide hydrochloride 163

LC/MS (method E) 0.52 min; m/z 349 (M + H) Used VII-7 Note 6, 7 (priorto HCl salt formation, the freebase was chromatographed on silica usingEtOAc/MeOH) 4′-(2-{[(3-fluorophenyl) methyl]amino}ethyl)-3-biphenylcarboxamide hydrochloride 164

LC/MS (method E) 0.56 min; m/z 399 (M + H) Used VII-7 Note 4, 7 (priorto HCl salt formation, the freebase was chromatographed on silica usingEtOAc/MeOH) 4′-[2-({[2-(trifluoromethyl) phenyl]methyl}amino)ethyl]-3-biphenylcarboxamide hydrochloride 165

LC/MS (method B) 2.17 min; m/z 373 (M + H) Used VII-7 and III-1 Step 1Intermed. Note 4 3′-{2-[(4,4-dimethylcyclohexyl)amino]ethyl}-3-biphenylcarboxamide trifluoroacetate 166

LC/MS (method B) 2.06 min; m/z 357 (M + H) Used VII-7 Note 43′-[2-(2,3-dihydro-1H-inden-2- ylamino)ethyl]-3-biphenylcarboxamidetrifluoroacetate 167

LC/MS (method B) 2.09 min; m/z 337 (M + H) Used VII-7 Note 43′-{2-[(cyclohexylmethyl)amino]ethyl}-3- biphenylcarboxamidetrifluoroacetate 168

LC/MS (method B) 2.23 min; m/z 351 (M + H) Used VII-7 Note 43′-{2-[(2-cyclohexylethyl)amino]ethyl}-3- biphenylcarboxamidetrifluoroacetate 169

LC/MS (method B) 2.17 min; m/z 373 (M + H) Used VII-7 Note 43′-{2-[(3-methylbutyl)amino]ethyl}-3- biphenylcarboxamidetrifluoroacetate Note 1 PS—BH₃CN = polymer-supported trialkylammoniumcyanoborohydride (novabiochem A30113). Note 2 Prepared using aconventional reducing agent (1.1 equiv NaBH₃CN) in THF/MeOH/HOAc(5:2:0.5 respectively). After stirring 3 d, the mixture was concentratedin vacuo, and partitioned between CH₂Cl₂/1M NaOH. The layers wereseparated, the aqueous layer was extracted with CH₂Cl₂ (×2), combinedorganics were washed (water, brine), dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by flash chromatography(EtOAc/hexanes). HCl (ca. 4 equiv of a 4M solution in dioxane) was addedto column eluent containing the desired product, affording the titlecompound as a cream-colored solid. The corresponding TFA salt of thetitle compound has also been prepared from I-VII-9 without isolation ofVII-4 (cf. Note 3). Note 3 The deprotected form of Formula VII was notcharacterized. The crude TFA salt of VII obtained from acidolysis of aBoc protecting group (TFA/Et₃SiH/CH₂Cl₂) was either admixed with anequimolar amount of Et₃N, or subjected to a basic aqueous workup(CHCl₃/satd Na₂CO₃) to obtain crude Formula VII which was used directlyfor reductive alkylation. Note 4 ‘MP—BH₃CN’ (Argonaut Technologies800407) was used as reducing agent (instead of ‘PS—BH₃CN’), and MeOH/THFcontaining ca. 5% HOAc was used as solvent (instead ofMeOH/CH₂Cl₂/HOAc). Note 5 Some dialkylated product was also produced inthis reaction. Note 6 Prepared using the standard reductive alkylationreagent sodium triacetoxyborohydride (1.5-3 eq) and (1-3 eq) of aldehydeto amine (VII-2). Note 7 A base extractive workup was performed and theorganics subjected to HCl in Et₂O or dioxane and the precipitatefiltered to give the title compound as the HCl salt. Note 8 Instead ofHPLC purification the crude material was subjected to silicachromatography using EtOAc/MeOH followed by recrystallization fromCH₂Cl₂/Hexane.

General Method 5 for Preparation of Compounds of Formula I Compounds ofFormula I Prepared According to General Method 5 Procedures Example 1703′-({[(4,4-dimethylcyclohexyl)methyl]amino}methyl)-2-methyl-4-biphenylcarboxamidehydrochloride

A mixture of 3′-formyl-2-methyl-4-biphenylcarboxamide (0.15 g, 0.63mmol; Ex. IX-23), 4,4-dimethylcyclohexylmethylamine hydrochloride (0.28g, 1.6 mmol; Ex III-1) and acetic acid (4 drops) in methanol was stirredat room temperature for 30 min. Sodium triacetoxyborohydride (0.34 g,1.6 mmol) was added in one portion and the mixture was stirred at roomtemperature for 72 hr. Water (10 mL) was added and the mixture wasstirred at room temperature for 2 hr. The mixture was concentrated invacuo to remove the methanol and the residue was taken up in a mixtureof ethyl acetate and 5% Na₂CO₃ (aq). The aqueous phase was extractedwith ethyl acetate. The combined organic phase was washed with brine,silica gel was added and the mixture was concentrated in vacuo.

The residue was purified by flash chromatography (CH₂Cl₂/MeOH). Thefreebase product obtained was dissolved in acetonitrile, filtered, andHCl was added (1M in Et₂O) until turbid, and allowed to stand at roomtemperature. Precipitated solid was collected by filtration, washed with(Et₂O) and air-dried to give the title compound as a white solid. LC/MS(method A) 1.90 min; m/z 365 (M+H).

Example 171 2:4′-[(2,3-Dihydro-1H-inden-2-ylamino)methyl]-3-biphenyl-carboxamidetrifluoroacetate

To a solution of 4′-formyl-3-biphenylcarboxamide (0.056 g; 0.25 mmol;Ex. IX-1) in MeOH/CH₂Cl₂/HOAc (5% v/v HOAc in 1:1 MeOH/CH₂Cl₂, 3 mL) atroom temperature was added 2-aminoindane (0.375 mmol; Note 1), followedby PS-BH₃CN (0.30 g; see Note 2). The mixture was agitated overnight,resin was removed by filtration and the filtrate was concentrated invacuo. The residue was purified by preparative HPLC (C-18 column,MeCN/H₂O gradient with 0.1% TFA additive) affording the final compoundas a colorless solid (Note 3). LC/MS (method A) 1.58 min, m/z 343 (M+H,57%), 210 ([M−aminoindane]+H, 100%).

-   Note 1 2-aminoindane hydrochloride was admixed with an equimolar    amount of Et₃N in CH₂Cl₂ before mixing with IX-1.-   Note 2 ‘PS-BH₃CN’=polymer-supported trialkylammonium    cyanoborohydride reagent (novabiochem A30113). An excess of PS-BH₃CN    was used (est. 3-5 equiv BH₃CN based on benzaldehyde starting    materials).-   Note 3 The title compound (as HCl salt) was also prepared using    solution-phase conditions similar to Example 172 below.

Example 1724′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3-biphenyl-carboxamidehydrochloride

A mixture of 4′-formyl-3-biphenylcarboxamide (0.576 g; 2.56 mmol; ExIX-1), 4,4-dimethylcyclohexylamine (0.390 g; 3.07 mmol; Note 1), andTsOH.H₂O (0.049 g; 0.26 mmol) in PhH (15 mL) was heated under refluxovernight, using a Dean-Stark trap to remove water. Upon cooling,volatiles were removed in vacuo, the residue was dissolved in 2.5% HOAcin MeOH (20 mL), and NaBH₃CN (0.17 g; 2.8 mmol) was added in oneportion. The mixture was stirred at room ca. 1 h (Note 2). The mixturewas concentrated in vacuo, the residue was partitioned between CH₂Cl₂/1MNaOH and the layers were separated. The organic layer was washed (H₂O,brine), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by preparative HPLC (C-18 column, MeCN/H₂O gradientwith 0.1% TFA additive); eluent containing desired product was pouredinto EtOAc/satd Na₂CO₃, layers were separated, the organic layer waswashed with brine and dried over Na₂SO₄. HCl (1 mL of a 4M solution indioxane) was added to the dried extract and the mixture was concentratedin vacuo, affording the title compound as a colorless solid (Note 3).LC/MS (method A) 2.06 min, m/z 337 (M+H).

-   Note 1 Ex III-1 was freebased before use by partitioning between    Et₂O and satd Na₂CO₃, separating layers, drying the organic layer    over Na₂SO₄ and concentrating in vacuo.-   Note 2 An aliquot of the reaction mixture after 45 min indicated    complete conversion.-   Note 3 The title compound was also prepared as a TFA salt according    to General Method 3.

Compounds of Formula I Prepared By General Method 5

The following examples were prepared from the appropriate compounds ofFormula IX and III in a manner similar to one of the representativeexamples given above; any significant deviations are noted below table.Compounds of Formula III which are readily available from commercialsources are not listed in the table.

TABLE 5 Compounds of Formula I from Compounds of Formula IX Ex Structureand Name Characterization Data Comments 173

LC/MS (method A) 1.76 min, m/z 351 (M + H) Used IX-3 and III-1 GeneralMethod: Example 171 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-6-methyl-3- biphenylcarboxamide trifluoroacetate 174

LC/MS (method A) 1.66 min, m/z 337 (M + H) Used IX-1 and III-3 GeneralMethod: Example 171 rac 4′-{[(3,3-dimethylcyclo- hexyl)amino]methyl}-3-biphenylcarboxamide trifluoroacetate 175

LC/MS (method A) 1.57 min, m/z 323 (M + H) Used IX-1 General Method:Example 171 4′-{[(cyclohexylmethyl)amino]methyl}- 3-biphenylcarboxamidetrifluoroacetate 176

LC/MS (method A) 1.45 min, m/z 335 (M + H) Used IX-1 General Method:Example 171 4′-({[(3-fluorophenyl)methyl]amino}methyl)-3-biphenylcarboxamide trifluoroacetate 177

LC/MS (method A) 1.51 min, m/z 331 (M + H) Used IX-1 General Method:Example 171 4′-{[(2-phenylethyl)amino]methyl}-3- biphenylcarboxamidetrifluoroacetate 178

LC/MS (method A) 1.72 min, m/z 351 (M + H) Used IX-4 and III-1 GeneralMethod: Example 171 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2′-methyl-3- biphenylcarboxamide trifluoroacetate 179

LC/MS (method C) 2.10 min, m/z 337 (M + H) Used IX-1 General Method:Example 171 4′-{[(cycloheptylmethyl)amino]methyl}- 3-biphenylcarboxamidetrifluoroacetate 180

LC/MS (method C) 2.09 min, m/z 337 (M + H) Used IX-1 General Method:Example 171 4′-[(cyclooctylamino)methyl]-3- biphenylcarboxamidetrifluoroacetate 181

LC/MS (method C) 2.09 min, m/z 361 (M + H) Used IX-1 General Method:Example 171 4′-[(tricyclo[3.3.1.13,7]dec-1-ylamino)methyl]-3-biphenyl-carboxamide trifluoroacetate 182

LC/MS (method C) 2.22 min, m/z 363 (M + H) Used IX-1 General Method:Example 171 4′-({[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}methyl)- 3-biphenyl-carboxamidetrifluoroacetate 183

LC/MS (method C) 2.11 min, m/z 337 (M + H) Used IX-5 and III-1 GeneralMethod: Example 171 3′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-3-biphenyl-carboxamide trifluoroacetate 184

LC/MS (method C) 2.10 min, m/z 337 (M + H) Used IX-6 and III-1 GeneralMethod: Example 171 3′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-4-biphenyl- carboxamide trifluoroacetate 185

LC/MS (method C) 1.94 min, m/z 297 (M + H) Used IX-1 General Method:Example 171 4′-{[(3-methylbutyl)amino]methyl}-3- biphenylcarboxamidetrifluoroacetate 186

LC/MS (method C) 1.89 min, m/z 297 (M + H) Used IX-6 General Method:Example 171 3′-{[(3-methylbutyl)amino]methyl}-4- biphenylcarboxamidetrifluoroacetate 187

LC/MS (method A) 1.37 min, m/z 360 (M + H) Used IX-7 and III-1 GeneralMethod: Example 171 N-{[3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-4,4-dimethylcyclohexanamine trifluoroacetate 188

LC/MS (method A) 1.15 min, m/z 366 (M + H) Used IX-7 General Method:Example 171 N-{[3′-(1H-imidazol-2-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine trifluoroacetate 189

LC/MS (method A) 1.61 min, m/z 357 (M + H) Used IX-4 General Method:Example 171 4′-[(2,3-dihydro-1H-inden-2- ylamino)methyl]-2′-methyl-3-biphenylcarboxamide trifluoroacetate 190

LC/MS (method A) 1.49 min, m/z 311 (M + H) Used IX-4 General Method:Example 171 2′-methyl-4′-{[(3-methylbutyl)-amino]methyl}-3-biphenyl-carboxamide trifluoroacetate 191

LC/MS (method C) 2.13 min, m/z 367 (M + H) Used IX-8 and III-1 GeneralMethod: Example 171 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2′-(methyloxy)-3-biphenyl carboxamide trifluoroacetate 192

LC/MS (method C) 2.17 min, m/z 371 (M + H) Used IX-9 and III-1 GeneralMethod: Example 171 2′-chloro-4′-{[(4,4-dimethyl-cyclohexyl)amino]methyl}-3-biphenylcarboxamide trifluoroacetate 193

LC/MS (method C) 1.99 min, m/z 323 (M + H) Used IX-1 General Method:Example 171 4′-[(cycloheptylamino)methyl]-3- biphenylcarboxamidetrifluoroacetate 194

LC/MS (method C) 2.18 min, m/z 337 (M + H) Used IX-1 and III-7 GeneralMethod: Example 171 4′-{[(2-cyclohexylethyl)amino]methyl}-3-biphenylcarboxamide trifluoroacetate 195

LC/MS (method D) 2.05 min, m/z 355 (M + H) Used IX-10 and III-1 GeneralMethod: Example 171 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2′-fluoro-3-biphenyl-carboxamide trifluoroacetate 196

LC/MS (method D) 1.77 min, m/z 345 (M + H) Used IX-1 and 4,4-difluorocyclohexylamine hydrochloride (commercial). General Method:Example 171 4′-{[(4,4- difluorocyclohexyl)amino]methyl}-3-biphenylcarboxamide trifluoroacetate 197

LC/MS (method D) 1.57 min, m/z 359 (M + H) Used IX-2 and 4,4-difluorocyclohexylamine hydrochloride (commercial). General Method:Example 171 4′-{[(4,4- difluorocyclohexyl)amino]methyl}-2-methyl-3-biphenyl-carboxamide trifluoroacetate 198

LC/MS (method D) 1.87 min, m/z 357 (M + H) Used IX-2 General Method:Example 171 4′-[(2,3-dihydro-1H-inden-2-ylamino) methyl]-2-methyl-3-biphenylcarboxamide trifluoroacetate 199

LC/MS (method B) 2.16 min, m/z 351 (M + H) Used IX-16 and III-1 GeneralMethod: Example 171 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-3′-methyl-3-biphenyl-carboxamide trifluoroacetate 200

LC/MS (method B) 2.15 min, m/z 351 (M + H) Used IX-17 and III-1 GeneralMethod: Example 171 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-4-methyl-3-biphenyl-carboxamide trifluoroacetate 201

LC/MS (method B) 2.08 min, m/z 355 (M + H) Used IX-12 and III-1 GeneralMethod: Example 171 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2-fluoro-3-biphenyl-carboxamide trifluoroacetate 202

LC/MS (method B). 1.63 min, m/z 357 (M + H). Used IX-23 General Method:Example 170 3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2-methyl-4-biphenyl- carboxamide hydrochloride 203

LC/MS (method B). 1.82 min, m/z 351 (M + H). Used IX-23 and III-7General Method: Example 170 3′-{[(2-cyclohexylethyl)amino]methyl}-2-methyl-4-biphenylcarboxamide hydrochloride 204

LC/MS (method B). 1.61 min, m/z 337 (M + H). Used IX-23 General Method:Example 170 3′-{[(cyclohexylmethyl)amino]methyl}-2-methyl-4-biphenylcarboxamide hydrochloride 205

LC/MS (method A) 1.89 min; m/z 370 Used methyl 4-(5- formyl-2-thienyl)-benzoate (commercial) General Method: Example 170 Used DCE as solvent.methyl 4-[5-({[2-(3-fluorophenyl) ethyl]amino}methyl)-2-thienyl]-benzoate 206

LC/MS (method A) 1.81 min; m/z 318 Used methyl 4-(5- formyl-2-thienyl)benzoate (commercial) General Method: Example 170 Used DCE assolvent. methyl 4-[5-({[2-(2-thienyl)ethyl]amino}methyl)-2-thienyl]-benzoate 207

LC/MS (method D) 2.08 min, m/z 351 (M + H). Used IX-203 and III-1General Method: Example 171 2-(4′-{[(4,4-dimethyl-cyclohexyl)amino]methyl}-3- biphenylyl)acetamide trifluoroacetate 208

LC/MS (method D) 2.14 min, m/z 405 (M + H). Used IX-54 and III-1 GeneralMethod: Example 171 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2′-(trifluoro-methyl)-3- biphenylcarboxamidetrifluoroacetate 209

LC/MS (method A) 1.77 min; m/z 360 (M + H). Used IX-18 and III-1 GeneralMethod: Example 171 N-{[4′-(1H-imidazol-2-yl)-3- biphenylyl]methyl}-4,4-dimethylcyclohexanamine trifluoroacetate 210

LC/MS (method A) 1.65 min; m/z 366 (M + H). Used IX-18 General Method:Example 171 N-{[4′-(1H-imidazol-2-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H- inden-2-amine trifluoroacetate 211

LC/MS (method A) 2.05 min; m/z 361 (M + H). Used IX-1 and III-10 GeneralMethod: Example 171 4′-{[(5-fluoro-2,3-dihydro-1H-inden-2-yl)amino]methyl}-3- biphenylcarboxamide hydrochloride 212

LC/MS (method A) 2.03 min; m/z 373 (M + H). Used IX-1 and III-14 GeneralMethod: Example 171 4′-({[4-(methyloxy)-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3- biphenylcarboxamide hydrochloride 213

LC/MS (method A) 1.99 min; m/z 372 (M + H). Used IX-1 and III-13 GeneralMethod: Example 171 4′-({[5-(methyloxy)-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3- biphenylcarboxamide hydrochloride 214

LC/MS (method A) 1.9 min; m/z 403 (M + H). Used IX-1 and III-15 GeneralMethod: Example 171 4′-({[5,6-bis(methyloxy)-2,3-dihydro-1H-inden-2-yl]amino}-methyl)-3- biphenylcarboxamide hydrochloride 215

LC/MS (method A) 2.28 min; m/z 419 (M + H). Used IX-56 and III-1 GeneralMethod: Example 171 Note 1, 2 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-2- methyl-3′-(trifluoromethyl)-3-biphenylcarboxamide hydrochloride 216

LC/MS (method B) 2.22 min; m/z 351 (M + H). Used IX-11 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-5- methyl-3-biphenyl-carboxamidetrifluoroacetate 217

LC/MS (method B) 2.14 min; m/z 357 (M + H). Used IX-11 General Method:Example 171 Note 1, 2 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-5-methyl-3- biphenylcarboxamide hydrochloride 218

LC/MS (method B) 1.99 min; m/z 361 (M + H). Used IX-12 General Method:Example 171 Note 1, 2 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2-fluoro-3- biphenylcarboxamide hydrochloride 219

LC/MS (method B) 2.33 min; m/z 405 (M + H). Used IX-55 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3′- (trifluoromethyl)-3-biphenylcarboxamide trifluoroacetate 220

LC/MS (method B) 2.23 min; m/z 411 (M + H). Used IX-55 General Method:Example 171 Note 1 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3′-(trifluoro-methyl)-3- biphenylcarboxamidetrifluoroacetate 221

LC/MS (method B) 2.06 min; m/z 371 (M + H). Used IX-13 and III-1 GeneralMethod: Example 171 Note 1, 2 Also 170 (Note 3)2-chloro-4′-{[(4,4-dimethyl- cyclohexyl)amino]methyl}-3-biphenylcarboxamide hydrochloride 222

LC/MS (method B) 1.94 min; m/z 377 (M + H). Used IX-13 General Method:Example 171 Note 1, 2 2-chloro-4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3- biphenylcarboxamide hydrochloride 223

LC/MS (method A) 2.1 min; m/z 367 (M + H). Used IX-14 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2-(methyloxy)-3- biphenylcarboxamide trifluoroacetate 224

LC/MS (method A) 2.01 min; m/z 373 (M + H). Used IX-14 General Method:Example 171 Note 1 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2-(methyloxy)-3- biphenylcarboxamide trifluoroacetate225

LC/MS (method A) 2.13 min; m/z 355 (M + H). Used IX-1 and III-1 GeneralMethod: Example 171 Note 1, 2 Also 170 (Note 3)4′-{[(4,4-dimethylcyclohexyl)- amino]methyl}-3′-fluoro-3-biphenylcarboxamide trifluoroacetate 226

LC/MS (method A) 2.02 min; m/z 361 (M + H). Used IX-1 General Method:Example 171 Note 1, 2 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3′-fluoro-3- biphenylcarboxamide hydrochloride 227

LC/MS (method A) 2.21 min; m/z 373 (M + H). Used IX-47 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2′,3′-difluoro-3- biphenylcarboxamide trifluoroacetate 228

LC/MS (method A) 2.15 min; m/z 391 (M + H). Used IX-46 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2,2′,3′-trifluoro-3-biphenyl- carboxamide trifluoroacetate 229

LC/MS (method A) 2.1 min; m/z 377 (M + H). Used IX-44 General Method:Example 171 Note 1 3′-chloro-4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3- biphenylcarboxamide trifluoroacetate 230

LC/MS (method B) 2.05 min; m/z 361 (M + H). Used IX-1 and (S)-III- 11General Method: Example 170 Note 4 4′-({[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3- biphenylcarboxamide hydrochloride 231

LC/MS (method B) 2.01 min; m/z 361 (M + H). Used IX-1 and (R)-III- 11General Method: Example 170 Note 4 4′-({[(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}methyl)-3- biphenylcarboxamide hydrochloride 232

LC/MS (method A) 2.01 min; m/z 379 (M + H). Used IX-1 and III-9 GeneralMethod: Example 171 Note 1 4′-{[(5,6-difluoro-2,3-dihydro-1H-inden-2-yl)amino]methyl}-3- biphenylcarboxamide trifluoroacetate 233

LC/MS (method A) 1.84 min; m/z 368 (M + H). Used IX-1 and III-12 GeneralMethod: Example 171 Note 1, 2 4′-{[(5-cyano-2,3-dihydro-1H-inden-2-yl)amino]methyl}-3- biphenylcarboxamide hydrochloride 234

LC/MS (method A) 2.01 min; m/z 357 (M + H). Used IX-1 and III-16 GeneralMethod: Example 171 Note 1 4′-{[(2-methyl-2,3-dihydro-1H-inden-2-yl)amino]methyl}-3- biphenylcarboxamide trifluoroacetate 235

LC/MS (method A) 1.88 min; m/z 395 (M + H). Used IX-13 and (S)-III- 11General Method: Example 171 Note 1 2-chloro-4′-({[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}-methyl)- 3-biphenylcarboxamidetrifluoroacetate 236

LC/MS (method A) 1.88 min; m/z 395 (M + H). Used IX-13 and (R)-III- 11General Method: Example 171 Note 1 2-chloro-4′-({[(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amino}-methyl)- 3-biphenyl-carboxamidetrifluoroacetate 237

LC/MS (method A) 2.14 min; m/z 355 (M + H). Used IX-48 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-5- fluoro-3-biphenyl-carboxamidetrifluoroacetate 238

LC/MS (method A) 2.24 min; m/z 371 (M + H). Used IX-49 and III-1 GeneralMethod: Example 171 Note 1 5-chloro-4′-{[(4,4-dimethyl-cyclohexyl)amino]methyl}-3- biphenylcarboxamide trifluoroacetate 239

LC/MS (method A) 2.3 min; m/z 405 (M + H). Used IX-50 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-5-(trifluoro-methyl)-3- biphenyl-carboxamidetrifluoroacetate 240

LC/MS (method A) 1.9 min; m/z 338 (M + H). Used IX-45 and III-1 GeneralMethod: Example 171 Note 1 5-(4-{[(4,4-dimethylcyclohexyl)-amino]methyl}phenyl)-3- pyridinecarboxamide trifluoroacetate 241

LC/MS (method A) 2.04 min; m/z 338 (M + H). Used IX-51 and III-1 GeneralMethod: Example 171 Note 1, 2 6-(4-{[(4,4-dimethylcyclohexyl)-amino]methyl}phenyl)-2- pyridinecarboxamide hydrochloride 242

LC/MS (method A) 1.95 min; m/z 338 (M + H). Used IX-52 and III-1 GeneralMethod: Example 171 Note 1 2-(4-{[(4,4-dimethylcyclohexyl)-amino]methyl}phenyl)-4- pyridinecarboxamide trifluoroacetate 243

LC/MS (method A) 2.03 min; m/z 389 (M + H). Used IX-38 and III-1 GeneralMethod: Example 171 Note 1 2-chloro-4′-{[(4,4-dimethyl-cyclohexyl)-amino]methyl}-3′-fluoro-3- biphenylcarboxamide trifluoroacetate 244

LC/MS (method A) 2.11 min; m/z 369 (M + H). Used IX-53 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)amino]methyl}-3′- fluoro-2-methyl-3-biphenylcarboxamide trifluoroacetate 245

LC/MS (method A) 2.13 min; m/z 373 (M + H). Used IX-41 and III-1 GeneralMethod: Example 171 Note 1 Also 170 (Note 4)4′-{[(4,4-dimethylcyclohexyl)- amino]methyl}-3′,5′-difluoro-3-biphenylcarboxamide trifluoroacetate 246

LC/MS (method A) 2.21 min; m/z 373 (M + H). Used IX-42 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-3′,5-difluoro-3-biphenyl- carboxamide trifluoroacetate 247

LC/MS (method A) 2.13 min; m/z 351 (M + H). Used IX-43 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-N-methyl-3- biphenylcarboxamide trifluoroacetate 248

LC/MS (method A) 2.21 min; m/z 371 (79%), 373 (100%)(M + H). Used IX-44and III-1 General Method: Example 171 Note 1, 23′-chloro-4′-{[(4,4-dimethyl- cyclohexyl)amino]methyl}-3-biphenylcarboxamide hydrochloride 249

LC/MS (method A) 1.9 min; m/z 366 (M + H). Used IX-57 General Method:Example 171 Note 1 N-{[3′-(1H-pyrazol-5-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H- inden-2-amine trifluoroacetate 250

LC/MS (method B) 2 min; m/z 338 (M + H). Used IX-40 and III-1 GeneralMethod: Example 171 Note 1 3-(6-{[(4,4-dimethylcyclohexyl)-amino]methyl}-3-pyridinyl)-benzamide trifluoroacetate 251

LC/MS (method B) 1.9 min; m/z 338 (M + H). Used IX-19 and III-1 GeneralMethod: Example 171 Note 1 3-(5-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2-pyridinyl)-benzamide trifluoroacetate 252

LC/MS (method B) 2.06 min; m/z 361 (M + H). Used IX-48 and III-1 GeneralMethod: Example 171 Note 1 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-5-fluoro-3- biphenylcarboxamide trifluoroacetate 253

LC/MS (method B) 2.09 min; m/z 379 (M + H). Used IX-42 General Method:Example 171 Note 1, 2 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3′,5-difluoro-3- biphenylcarboxamide hydrochloride 254

LC/MS (method B) 1.88 min; m/z 344 (M + H). Used IX-40 General Method:Example 171 Note 1 3-{6-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-pyridinyl}- benzamide trifluoroacetate 255

LC/MS (method B) 1.77 min; m/z 344 (M + H). Used IX-19 General Method:Example 171 Note 1 3-{5-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2-pyridinyl}- benzamide trifluoroacetate 256

LC/MS (method B) 1.92 min; m/z 395 (M + H). Used IX-39 General Method:Example 171 Note 1 2-chloro-4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3′-fluoro-3- biphenylcarboxamide trifluoroacetate 257

LC/MS (method A) 1.77 min; m/z 383 (M + H). Used IX-21 General Method:Example 171 Note 1 3-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-5- isoxazolamine trifluoroacetate 258

LC/MS (method A) 1.62 min; m/z 379 (M + H). Used IX-15 and (S)-III- 11General Method: Example 171 Note 1, 2 Also 170 (Note 3)3′-fluoro-4′-({[(2S)-5-fluoro-2,3- dihydro-1H-inden-2-yl]amino}-methyl)-3-biphenylcarboxamide hydrochloride 259

LC/MS (method A) 1.62 min; m/z 379 (M + H). Used IX-15 and (R)-III- 11General Method: Example 171 Note 1, 2 Also 170 (Note 3)3′-fluoro-4′-({[(2R)-5-fluoro-2,3- dihydro-1H-inden-2-yl]amino}-methyl)-3-biphenylcarboxamide hydrochloride 260

LC/MS (method E) 1.02 min; m/z 373 (M + H). Used IX-22 and III-1 GeneralMethod: Example 171 Note 1 4′-{[(4,4- dimethylcyclohexyl)amino]methyl}-2,3′-difluoro-3-biphenyl-carboxamide trifluoroacetate 261

LC/MS (method E) 0.94 min; m/z 379 (M + H). Used IX-22 General Method:Example 171 Note 1, 2 4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2,3′-difluoro-3- biphenylcarboxamide hydrochloride 262

LC/MS (method E) 0.63 min; m/z 317 (M + 1) Used IX-1 General Method:Example 171 Note 1, 4 4′-{[(phenylmethyl)amino]methyl}-3-biphenylcarboxamide 263

LC/MS (method E) 0.69 min; m/z 385 (M + 1) Used IX-1 General Method:Example 171 Note 1, 4 4′-[({[3-(trifluoromethyl)-phenyl]methyl}amino)methyl]-3- biphenyl-carboxamide 264

LC/MS (method E) 0.7 min; m/z 385 (M + 1) Used IX-1 General Method:Example 171 Note 1, 4 4′-[({[4-(trifluoromethyl)-phenyl]methyl}amino)methyl]-3- biphenyl-carboxamide 265

LC/MS (method E) 0.61 min; m/z 453 (M + 1) Used IX-1 General Method:Example 171 Note 1, 4 4′-[({[3,5-bis(trifluoromethyl)-phenyl]methyl}amino)methyl]-3- biphenyl-carboxamide 266

LC/MS (method E) 0.55 min; m/z 385 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-[({[2-(trifluoromethyl)-phenyl]methyl}amino)methyl]-3- biphenylcarboxamide hydrochloride 267

LC/MS (method E) 0.56 min; m/z 335 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-({[(4-fluorophenyl)methyl]-amino}methyl)-3-biphenyl- carboxamide hydrochloride 268

LC/MS (method E) 0.63 min; m/z 401 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-{[({3- [(trifluoromethyl)oxy]phenyl}methyl)amino]methyl}-3-biphenylcarboxamide hydrochloride 269

LC/MS (method E) 0.58 min; m/z 351 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-({[(3-chlorophenyl)methyl]-amino}methyl)-3-biphenyl- carboxamide hydrochloride 270

LC/MS (method E) 0.52 min; m/z 335 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-({[(2-fluorophenyl)methyl]-amino}methyl)-3-biphenyl- carboxamide hydrochloride 271

LC/MS (method E) 0.59 min; m/zz 401 (M + 1 Used IX-1 General Method:Example 171 Note 1, 5 4′-{[({2-[(trifluoromethyl)oxy]-phenyl}methyl)amino]methyl}-3- biphenylcarboxamide hydrochloride 272

LC/MS (method E) 0.54 min; m/z 351 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-({[(2-chlorophenyl)methyl]-amino}methyl)-3-biphenyl- carboxamide hydrochloride 273

LC/MS (method E) 0.56 min; m/z 385 and 387 (M + 1 Cl isotopes) Used IX-1General Method: Example 171 Note 1, 5 4′-({[(2,3-dichlorophenyl)-methyl]amino}methyl)-3- biphenylcarboxamide hydrochloride 274

LC/MS (method E) 0.66 min; m/z 331 (M + 1) Used IX-1 General Method:Example 171 Note 1, 4 4′-{[(1-phenylethyl)amino]-methyl}-3-biphenylcarboxamide 275

LC/MS (method E) 0.49 min; m/z 301 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-({[2-(methylthio)ethyl]-amino}methyl)-3-biphenyl- carboxamide hydrochloride 276

LC/MS (method E) 0.51 min; m/z 315 (M + 1) Used IX-1 General Method:Example 171 Note 1, 5 4′-({[3-(methylthio)propyl]-amino}methyl)-3-biphenyl- carboxamide hydrochloride (U24649- 165) 277

LC/MS (method E) 0.65 min; m/z 343 (M + 1) Used IX-1 General Method:Example 172 Note 6 4′-[(1H-benzimidazol-2-yl- amino)methyl]-3-biphenyl-carboxamide 278

LC/MS (method A) 1.52 min; m/z 377 (M + H). Used IX-24 General Method:Example 170 3-chloro-3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-4-biphenyl- carboxamide hydrochloride. 279

LC/MS (method A) 1.72 min; m/z 371 (M + H). Used IX-24 and III-7 GeneralMethod: Example 170 3-chloro-3′-{[(2-cyclohexylethyl)amino]methyl}-4-biphenyl- carboxamide hydrochloride. 280

LC/MS (method A) 1.71 min; m/z 371 (M + H). Used IX-24 and III-1 GeneralMethod: Example 170 3-chloro-3′-{[(4,4-dimethyl-cyclohexyl)amino]methyl}-4- biphenylcarboxamide hydrochloride. 281

LC/MS (method B) 1.53 min; m/z 373 (M + H). Used IX-25 General Method:Example 170 3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2-(methyloxy)-4- biphenylcarboxamide hydrochloride. 282

LC/MS (method A) 1.79 min; m/z 367 (M + H). Used IX-25 and III-7 GeneralMethod: Example 170 3′-{[(2-cyclohexylethyl)amino]methyl}-2-(methyloxy)-4-biphenyl- carboxamide hydrochloride 283

LC/MS (method A) 1.68 min; m/z 367 (M + H). Used IX-25 and III-1 GeneralMethod: Example 170 3′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2-(methyloxy)-4- biphenylcarboxamide hydrochloride. 284

LC/MS (method A) 1.65 min; m/z 377 (M + H). Used IX-26 General Method:Example 170 2-chloro-3′-[(2,3-dihydro-1H-inden-2- ylamino)methyl]-4-biphenylcarboxamide hydrochloride. 285

LC/MS (method A) 1.88 min; m/z 371 (M + H). Used IX-26 and III-7 GeneralMethod: Example 170 2-chloro-3′-{[(2-cyclohexyl- ethyl)amino]methyl}-4-biphenylcarboxamide hydrochloride. 286

LC/MS (method B) 1.72 min; m/z 371 (M + H). Used IX-26 and III-1 GeneralMethod: Example 170 2-chloro-3′-{[(4,4-dimethylcyclo-hexyl)amino]methyl}-4-biphenyl- carboxamide hydrochloride. 287

LC/MS (method A) 1.59 min; m/z 361 (M + H). Used IX-27 General Method:Example 170 3′-[(2,3-dihydro-1H-inden-2- ylamino)methyl]-4′-fluoro-4-biphenylcarboxamide hydrochloride. 288

LC/MS (method A) 1.80 min; m/z 355 (M + H). Used IX-27 and III-7 GeneralMethod: Example 170 3′-{[(2-cyclohexylethyl)amino]-methyl}-4′-fluoro-4-biphenyl-carboxamide hydrochloride. 289

LC/MS (method A) 1.72 min; m/z 355 (M + H). Used IX-27 and III-1 GeneralMethod: Example 170 3′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-4′-fluoro-4- biphenylcarboxamide hydrochloride 290

355 1.71 LC/MS (method A) min; m/z (M + H). Used IX-28 and III-7 GeneralMethod: Example 170 3′-{[(2-cyclohexylethyl)amino]-methyl}-2′-fluoro-4-biphenylcarboxamide hydrochloride 291

LC/MS (method A) 1.48 min; m/z 361 (M + H). Used IX-28 General Method:Example 170 3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2′-fluoro-4-biphenyl- carboxamide hydrochloride 292

LC/MS (method A) 1.63 min; m/z 355 (M + H). Used IX-28 and III-1 GeneralMethod: Example 170 3′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2′-fluoro-4-biphenyl- carboxamide hydrochloride 293

LC/MS (method A) 1.75 min; m/z 355 (M + H). Used IX-29 and III-7 GeneralMethod: Example 170 5′-{[(2-cyclohexylethyl)-amino]methyl}-2′-fluoro-4-biphenylcarboxamide hydrochloride 294

LC/MS (method A) 1.53 min; m/z 361 (M + H). Used IX-29 General Method:Example 170 5′-[(2,3-dihydro-1H-inden-2- ylamino)methyl]-2′-fluoro-4-biphenylcarboxamide hydrochloride 295

LC/MS (method A) 1.72 min; m/z 355 (M + H). Used IX-29 and III-1 GeneralMethod: Example 170 Note 6 5′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2′-fluoro-4- biphenylcarboxamide hydrochloride 296

LC/MS (method A) 1.89 min; m/z 371 (M + H). Used IX-30 and III-7 GeneralMethod: Example 170 3′-chloro-5′-{[(2-cyclohexyl-ethyl)amino]methyl}-4-biphenyl- carboxamide hydrochloride. 297

LC/MS (method A) 1.80 min; m/z 371 (M + H). Used IX-30 and III-1 GeneralMethod: Example 170 Note 6 3′-chloro-5′-{[(4,4-dimethyl-cyclohexyl)amino]methyl}-4- biphenylcarboxamide hydrochloride. 298

LC/MS (method A) 1.69 min; m/z 377 (M + H). Used IX-30 General Method:Example 170 3′-chloro-5′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-4-biphenyl- carboxamide hydrochloride. 299

LC/MS (method A) 1.80 min; m/z 369 (M + H). Used IX-31 and III-7 GeneralMethod: Example 170 3′-{[(2-cyclohexyl-ethyl)amino]-methyl}-2′-fluoro-2-methyl-4- biphenylcarboxamide hydrochloride. 300

LC/MS (method A) 1.62 min; m/z 375 (M + H). Used IX-31 General Method:Example 170 3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-2′-fluoro-2-methyl-4- biphenylcarboxamide hydrochloride.301

LC/MS (method A) 1.69 min; m/z 369 (M + H). Used IX-31 and III-1 GeneralMethod: Example 170 Note 6 3′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2′-fluoro-2-methyl-4-biphenyl- carboxamide hydrochloride. 302

LC/MS (method A) 1.74 min; m/z 367 (M + H). Used IX-32 and III-7 GeneralMethod: Example 170 5′-{[(2-cyclohexylethyl)-amino]methyl}-2′-(methyloxy)-4-biphenylcarboxamide hydrochloride. 303

LC/MS (method A) 1.70 min; m/z 367 (M + H). Used IX-32 and III-1 GeneralMethod: Example 170 Note 6 5′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-2′-(methyloxy)-4- biphenylcarboxamide hydrochloride. 304

LC/MS (method A) 0.69 min, m/z 382 (M + H). Used IX-34 General Method:Example 170 Note 7 1-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-1,3- dihydro-2H-imidazol-2-onehydrochloride 305

LC/MS (method A) 0.66 min, m/z 383 (M + H). Used IX-35 General Method:Example 170 Note 7 4-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-2,4- dihydro-3H-1,2,4-triazol-3-onehydrochloride 306

LC/MS (method A) 0.66 min, m/z 398 (M + H). Used IX-36 General Method:Example 170 Note 7 1-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-2,4- imidazolidinedione hydrochloride 307

LC/MS (method A) 0.71 min, m/z 338 (M + H). Used IX-37 General Method:Example 170 Note 7 1-{4′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-3-biphenylyl}-2- imidazolidinone hydrochloride 308

LC/MS (method A) 0.58 min, m/z 420 (M + H). Used IX-38 General Method:Example 170 Note 7 N-{[3′-(1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-4-biphenylyl]methyl}-2,3- dihydro-1H-inden-2-amine hydrochloride309

LC/MS (method A) 0.61 min, m/z 414 (M + H). Used IX-38 and III-1 GeneralMethod: Example 170 Note 7 N-{[3′-(1,1-dioxido-1,2,5-thia-diazolidin-2-yl)-4-biphenylyl]-methyl}- 4,4-dimethylcyclo-hexanaminehydrochloride 310

LC/MS (method A) 0.74 min, m/z 378 (M + H). Used IX-37 and III-1 GeneralMethod: Example 170 Note 7 1-(4′-{[(4,4-dimethylcyclohexyl)-amino]methyl}-3-biphenylyl)-2- imidazolidinone hydrochloride Note 1‘MP—BH₃CN’ polymer-supported cyanoborohydride (Argonaut Technologies p/n800407) was used as reducing agent (ca. 3 equiv BH₃CN), THF/MeOH/HOAcmixture (ca. 5% HOAc in 1:1 THF/MeOH) was used as solvent. Note 2Product was purified by flash chromatography (EtOAc/hexanes) usingamine-functionalized silica gel (Teledyne-Isco p/n 68-2203-102). HClsolution (4M in dioxane) was added to column eluent containing thedesired product and the whole was concentrated in vacuo, affording anHCl salt. Note 3 NaBH₃CN (1.2 equiv) was used as reducing agent, andTHF/MeOH/HOAc (ca. 5% HOAc in 1:1 THF/MeOH) was used as solvent. Note 4Title compounds were obtained as freebases from the crude reactionfiltrates, after concentration, by triturating with CH₂Cl₂, and dryingin vacuo at 60° C. overnight. Note 5 In those cases where the reactionproducts could not be resolved from impurities by chromatography, thecrude residues were subjected to standard N-Boc protection conditions(Boc₂O/Et₃N/CH₂Cl₂). The resulting carbamate was then purified by flashchromatography (EtOAc/hexanes), dissolved in CH₂Cl₂ and treated with HClin dioxane, effecting deprotection and affording the title compound asan HCl salt. Note 6 Amine hydrochloride salt used was admixed with Et₃Nbefore use. Note 7 Crude residues obtained after aqueous workup(Na₂CO₃/EtOAc) were taken up in dioxane and treated with HCl in Et₂O.Supernatant liquid was decanted away, and the precipitated solids wereair-dried, affording the title compounds as HCl salts.

General Method 6 for Preparation of Compounds of Formula I GeneralMethod 6: Preparation of 2,5-Substituted Furans Example 311 Preparationof 4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzamide

To a 50 mL sealed tube was added ethyl4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzoate (100mg, 0.27 mmol, Example X-1), 2.0 M MeOH/NH₃ (20 mL), and KCN (30 mg).The reaction mixture was stirred at 125° C. overnight. The crude mixturewas purified on RP-preparative HPLC to give 3 mg of4-[5-({[2-(3-fluorophenyl)ethyl]amino}methyl)-2-furanyl]benzamide. (M+1)339.23, 1.42 min (LC/MS method A)

The following were prepared in a manner similar to that described inGeneral Method 6 Example using the corresponding amine

TABLE 6 Compounds of Formula I from Compounds of Formula X viaAminolysis Ex. Structure and Name Characterization Data Method/Comments312

(M + H) 287, 1.24 min (LC/MS method A) Used Example X-24-(5-{[(3-methylbutyl)amino]methyl}-2-furanyl)benzamide trifluoroacetate

General Method 7: Deprotection of Compounds of Formula X to Compounds ofFormula I Example 313N-{[4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-aminehydrochloride

To a solution of(3-{3′-[(2,3-dihydro-1H-inden-2-ylamino)methyl]-4-biphenylyl}-1H-1,2,4-triazol-1-yl)methyl2,2-dimethylpropanoate (0.084 g, 0.17 mmol, Example X-3) in EtOH (1.5mL) was added a 4.37 M solution of NaOMe in MeOH (0.08 mL, 0.35 mmol).The mixture was stirred for 50 min at RT. A 1.2M solution ofconcentrated HCl in EtOH was added (1.2 mL), and the mixture was heatedat 80° C. for 1 h. The reaction mixture was cooled, diluted with water,and basified to a pH of 10 with addition of saturated Na₂CO₃ (aq). Themixture was extracted with EtOAc. The combined organic extracts werewashed with water and brine, dried with anhydrous Na₂SO₄, andconcentrated in vacuo. The residue was dissolved in CH₂Cl₂ and MeOH, and4N HCl in dioxane was added (0.2 mL). After stirring for 15 min, theprecipitate was filtered, washed with CH₂Cl₂, and dried, affording thetitle compound as a colorless solid (0.057 g, 89%). (M+H) 367, 1.74 min(LC/MS Method B).

TABLE 7 Compounds of Formula I from Compounds of Formula X viaN-deprotection Ex. Structure and Name Characterization DataMethod/Comments 314

(M + H) 385, 1.79 min (LC/MS Method B) Synthesized from X-4.N-{[4-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 315

(M + H) 385, 1.74 min (LC/MS Method B) Synthesized from X-5.N-{[2-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 316

(M + H) 381, 1.77 min (LC/MS Method B) Synthesized from X-6. EliminatedMeOH for salt formation.N-{[2′-methyl-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 317

(M + H) 375, 0.60 min (LC/MS Method F) Synthesized from X-7.4,4-dimethyl-N-{[2′-methyl-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}cyclohexanamine hydrochloride 318

(M + H) 375, 0.62 min (LC/MS Method F) Synthesized from X-8.(2-cyclohexylethyl){[2′-methyl-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}amine hydrochloride 319

(M + H) 385, 1.78 min (LC/MS Method B) Synthesized from X-9.N-{[2′-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 320

(M + H) 379, 0.61 min (LC/MS Method F) Synthesized from X-10.N-{[2′-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-4,4-dimethylcyclohexanamine hydrochloride 321

(M + H) 379, 0.61 min (LC/MS Method F) Synthesized from X-11. EliminatedMeOH for salt formation.(2-cyclohexylethyl){[2′-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}amine hydrochloride 322

(M + H) 403, 0.56 min (LC/MS Method F) Synthesized from X-12.N-{[2,2′-difluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 323

(M + H) 361, 0.59 min (LC/MS Method F) Synthesized from X-13.4,4-dimethyl-N-{[4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}cyclohexanamine hydrochloride 324

(M + H) 379, 0.58 min (LC/MS Method F) Synthesized from X-14. EliminatedMeOH for salt formation. N-{[2-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-4,4-dimethylcyclohexanamine hydrochloride 325

(M + H) 379, 0.60 min (LC/MS Method F) Synthesized from X-15. EliminatedMeOH for salt formation. (2-cyclohexylethyl){[2-fluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}amine hydrochloride 326

(M + H) 397, 0.59 min (LC/MS Method F) Synthesized from X-16. EliminatedMeOH for salt formation.N-{[2,2′-difluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-4,4-dimethylcyclohexanamine hydrochloride 327

(M + H) 399, 0.56 min (LC/MS Method F) Synthesized from X-17. EliminatedMeOH for salt formation.N-{[2-fluoro-2′-methyl-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 328

(M + H) 393, 0.59 min (LC/MS Method F) Synthesized from X-18. EliminatedMeOH for salt formation.N-{[2-fluoro-2′-methyl-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-4,4-dimethylcyclohexanamine hydrochloride 329

(M + H) 403, 0.56 min (LC/MS Method F) Synthesized from X-19. EliminatedMeOH for salt formation.N-{[2,4-difluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 330

(M + H) 397, 0.60 min (LC/MS Method F) Synthesized from X-20. EliminatedMeOH for salt formation.N-{[2,4-difluoro-4′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-4,4-dimethylcyclohexanamine hydrochloride 331

(M + H) 403, 0.71 min (LC/MS Method F) Synthesized from X-21. EliminatedMeOH for salt formation.N-{[2,4-difluoro-3′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 332

(M + H) 397, 0.76 min (LC/MS Method F) Synthesized from X-23. EliminatedMeOH for salt formation.(2-cyclohexylethyl){[2,4-difluoro-3′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}amine hydrochloride 333

(M + H) 385, 0.70 min (LC/MS Method F) Synthesized from X-24.N-{[2-fluoro-3′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 334

(M + H) 385, 1.81 min (LC/MS Method A) Synthesized from X-25. EliminatedMeOH for salt formation.N-{[4-fluoro-3′-(1H-1,2,4-triazol-3-yl)-3-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 335

LC/MS (method B) 2.26 min; m/z 361 (M + H) Synthesized from X-26(4,4-dimethylcyclohexyl){[3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}amine hydrochloride 336

LC/MS (method B) 2.17 min; m/z 367 (M + H) Synthesized from X-27N-{[3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 337

LC/MS (method A) 2.31 min; m/z 361 (M + H) Synthesized from X-28(4,4-dimethylcyclohexyl){[3′-(2H-1,2,3-triazol-4-yl)-4-biphenylyl]methyl}amine trifluoroacetate 338

LC/MS (method A) 2.21 min; m/z 367 (M + H) Synthesized from X-29N-{[3′-(2H-1,2,3-triazol-4-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine trifluoroacetate 339

LC/MS (method A) 1.66 min; m/z 386 (M + H) Synthesized from X-30N-{[2′-fluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine 340

LC/MS (method A) 1.61 min; m/z 399 (100%), 400 (21%), 402 (37%) (M + H)Synthesized from X-31 (N-{[2′-chloro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine 341

LC/MS (method A) 1.76 min; m/z 385 (M + H) Synthesized from X-32N-{[3-fluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine 342

0.71 min; m/z 403 (M + H) Synthesized from X-33 Note 2N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine hydrochloride 343

LC/MS (method A) 1.76 min; m/z 385 (M + H) Synthesized from X-34[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]{[3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}amine hydrochloride 344

LC/MS (method A) 1.74 min; m/z 385 (M + H) Synthesized from X-35[(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]{[3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}amine hydrochloride 345

LC/MS (method E) 0.59 min; m/z 397 (M + H) Synthesized from X-36N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-4,4-dimethylcyclohexanamine trifluoroacetate 346

LC/MS (method E) 0.72 min; m/z 421 (M + H) Synthesized from X-37{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}[(2R)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amine hydrochloride 347

LC/MS (method E) 0.56 min; m/z 421 (M + H) Synthesized from X-38{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}[(2S)-5-fluoro-2,3-dihydro-1H-inden-2-yl]amine trifluoroacetate 348

LC/MS (method E) 0.85 min; m/z 433 (M + H) Synthesized from X-39(2-cyclohexyl-2,2-difluoroethyl){[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}amine hydrochloride 349

LC/MS (method E) 0.6 min; m/z 397 (M + H) Synthesized from X-40(2-cyclohexylethyl){[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}amine trifluoroacetate 350

LC/MS (method E) 0.54 min; m/z 377 (M + H) Synthesized from X-41{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}(phenylmethyl)amine trifluoroacetate 351

LC/MS (method E) 0.71 min; m/z 391 (M + H) Synthesized from X-42N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2-phenylethanamine hydrochloride 352

LC/MS (method E) 0.57 min; m/z 405 (M + H) Synthesized from X-43N-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-3-phenyl-1-propanamine trifluoroacetate 353

LC/MS (method E) 0.62 min; m/z 423 (M + H) Synthesized from X-44{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}[(1R,2R,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]aminetrifluoroacetate Note1: Purified by reverse phase chromatography (CH₃CN/H₂O/TFA). Note 2: Thecrude product can also be isolated as diHCl salt straight from thereaction after one hour of stirring. Then recrystallized fromEtOH/HCl(aq).

LC/MS Method A (Standard Electrospray Method):

Mass Spectrometry is used to confirm peak identity withelectrospray+/−ionization scanning from 100-1000 m/z and DAD from220-400 nm. Phenomenex Luna column 4.6 mm by 2 cm, particle size 3 um,ambient temperature. Solvent flow at 2 ml/min. Gradient begins at 10%MeOH and goes linearly to 100% MeOH in 3 minutes, holds 100% MeOH for 1minute, making total chromatogram time 4 minutes. 2 ul sample injection.Aqueous mobile phase contains 0.1% v/v Formic Acid and MeOH contains0.075% v/v Formic Acid.

LC/MS Method B (Standard APCI Method):

Mass Spectrometry is used to confirm peak identity withAPCI+/−ionization scanning from 100-1000 m/z and DAD from 220-400 nm.Phenomenex Luna column 4.6 mm by 2 cm, particle size 3 um, ambienttemperature. Solvent flow at 2 ml/min. Gradient begins at 10% MeOH andgoes linearly to 100% MeOH in 3 minutes, holds 100% MeOH for 1 minute,making total chromatogram time 4 minutes. 2 ul sample injection. Aqueousmobile phase contains 0.1% v/v Formic Acid and MeOH contains 0.075% v/vFormic Acid.

LC/MS Method C (Polar APCI Method):

Mass Spectrometry is used to confirm peak identity withAPCI+/−ionization scanning from 100-1000 m/z and DAD from 220-400 nm.Phenomenex Luna column 4.6 mm by 2 cm, particle size 3 um, ambienttemperature. Solvent flow at 2 ml/min. Gradient begins at 2% MeOH andgoes linearly to 26% MeOH in 1 minute, then goes linearly from 26% MeOHto 100% MeOH in 2 min., then holds 100% MeOH for 1 minute, making totalchromatogram time 4 minutes. 2 ul sample injection. Aqueous mobile phasecontains 0.1% v/v Formic Acid and MeOH contains 0.075% v/v Formic Acid.

LC/MS Method D (Polar Electrospray Method):

Mass Spectrometry is used to confirm peak identity withelectrospray+/−ionization scanning from 100-1000 m/z and DAD from220-400 nm. Phenomenex Luna column 4.6 mm by 2 cm, particle size 3 um,ambient temperature. Solvent flow at 2 ml/min. Gradient begins at 2%MeOH and goes linearly to 26% MeOH in 1 minute, then goes linearly from26% MeOH to 100% MeOH in 2 min., then holds 100% MeOH for 1 minute,making total chromatogram time 4 minutes. 2 ul sample injection. Aqueousmobile phase contains 0.1% v/v Formic Acid and MeOH contains 0.075% v/vFormic Acid.

LC-MS Method E (Standard Electrospray Fast Mass Spec Method):

Electrospray+ionization scanning from 100-800 m/z with DAD sum from220-400 nm. Waters Acquity HPLC column 2.1 mm by 5 cm, particle size 1.7um, temperature at 40 degrees C. Solvent flow at 1 ml/min. Gradientbegins at 6% ACN and goes linearly to 70% ACN in 0.57 minute; gradientthen goes linearly to 99% ACN from 0.57 minute to 1.06 minute, holds 99%ACN until 1.5 minute, making total chromatogram time 1.5 minutes. 1.5 ulsample injection. Aqueous mobile phase contains 0.1% v/v Formic Acid andACN contains trace v/v Formic Acid.

LC-MS Method F (Standard APCI Fast Mass Spec Method):

Mass Spectrometry is used to confirm peak identity withAPCI+/−ionization scanning from 100-1000 m/z and DAD from 220-400 nm.Column is Waters Acquity BEH UPLC column 2.1 mm by 5 cm, particle size1.7 um, temperature at 25 degrees C. Solvent flow at 1 ml/min. Gradientbegins at 6% ACN and goes linearly to 70% ACN in 0.57 minute; gradientthen goes linearly to 99% ACN from 0.57 minute to 1.06 minute, holds 99%ACN until 1.5 minute, making total chromatogram time 1.5 minutes. 1.5 ulsample injection. Aqueous mobile phase contains 0.1% v/v Formic Acid andACN contains trace v/v Formic Acid.

ABBREVIATIONS

anhyd anhydrous

APCI atmospheric pressure chemical ionization

app. apparent

BH₃.DMS borane-dimethyl sulfide complex

(Boc)₂O di-tert-butyl dicarbonate

BOC tert-Butoxycarbonyl

br. broad

ca. approximately

cf. compare to

conc concentrated

Cbz benzyloxycarbonyl

DCE dichloroethane

DIBAL-H diisobutylaluminum hydride

DIPEA diisopropylethylamine

DMAP 4-dimethylaminopyridine

DME 1,2-dimethoxyethane

DMF dimethylformamide

DMSO dimethylsulfoxide

dppf 1,1′-Bis(diphenylphosphino)ferrocene

ESI electrospray ionization

Et₂O diethyl ether

Et₃N triethylamine

Et₃SiH triethylsilane

EtOAc ethyl acetate

EtOH ethanol

h hour

HOAc acetic acid

in vacuo under reduced pressure

KOAc potassium acetate

LC/MS liquid chromatography-mass spectrometry

MeCN acetonitrile

MeOH methanol

min minute

μwave microwave

N.B. note bene (attention)

PhH benzene

PhMe toluene

POM pivaloyloxymethyl

PPA polyphosphoric acid

PS-BH₃CN (polystyrylmethyl)trimethylammonium cyanoborohydride

PTFE (poly)tetrafluoroethylene polymer

Ra—Ni Raney Nickel

Rochelle's salt potassium sodium tartrate

RP-HPLC reverse phase high pressure liquid chromatography

rt room temperature

sat'd saturated

SEM 2-(trimethylsilyl)ethoxymethyl

S-Phos 2-(2′,6′-dimethoxybiphenyl)di-cyclohexylphosphine

t-Bu tert-butyl

t_(R) retention time on the LC/MS instrument

Tf₂O trifluoromethanesulfonic anhydride

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

TsOH p-toluenesulfonic acid

Method of Testing Compounds of the Invention

Materials

LEADSeeker WGA™ beads and GTPgS35 were purchased from AmershamBioscience (Piscataway, N.J.). GDP, Saponin™, DAMGO™, Met-Enkephalin,Dynorphin A, NaCl and HEPEST™ were purchased from SIGMA (St Louis, Mo.).MgCl2 was purchased from J. T. Baker (Pillipsburg, N.J.). Opioidmembranes, hOPRD, hOPRK and hOPRM were prepared at GlaxoSmithkline(Harlow, UK). Cells expressing opioid receptors were prepared asmembranes using standard methodologies. Collected cell pellets werehomogenized with a blender followed by a low speed centrifugation toremove nuclei and unbroken cells. This was followed by two high speedspins and washes homogenized with a dounce homogenizer. Membranes werestored at −70 C and are stable for at least six months.

Assay buffer; 20 mM HEPES, 10 mM MgCL2, and 100 mM NaCl dissolved inlabgrade water, pH 7.4 with KOH.

[35S]GTPgammaS Binding Assay Measured by LEADseeker SPA (384 Well)

Dilute GTPgS35 1:900 in assay buffer in half of required final assayvolume (volume A). Add the corresponding standard agonist,Met-Enkephalin (hOPRD), Dynorphin A (hOPRK) or DAMGO (hOPRM) to give asolution concentration of 8×[EC50], for a final assay concentration of4×[EC50] to volume A. Resuspend LEADSeeker beads in assay buffer inorder to generate a 40 mg/mL stock solution. GDP is dissolved in assaybuffer at 1 mM. Add beads (100 microgram/well final) to assay buffercontaining saponin (60 microgram/mL) in half of final assay volume(volume B). Mix well by vortexing. Add opioid membranes to eachrespective volume B, for a final assay concentration of 1.5microgram/well (hOPRD), 1.0 microgram/well (hOPRK), and 1.5microgram/well (hOPRM). Continuously mix the bead/membrane solution(volume B) for 30 min prior to adding to the GTPgS35 solution (volume A)in a 1:1 ratio using a stir plate. Just prior to adding bead/membranesolution to the GTPgS35 solution, add GDP to volume B at 20 microMolar(10 microMolar final assay concentration). Add the bead/membranesolution to the GTPgS35 solution in a 1:1 ratio. Add 10 microLiters ofthe bead/membrane/GTPgS35 mix to the assay plate using a Multidrop(TITERTEK™, multi-channel liquid dispensing equipment). Agitation of thesolution is needed to prevent the beads/membrane from settling at thebottom. Plates are sealed, spun at 1000 rpm for 2 mins, tapped on sideto agitate and incubated at room temperature for 5 hours. Plates arethen imaged using a VIEWLUX PLUS™, plate based imaging equipment Imager(Perkin Elmer).

Acceptable compounds of the invention have an activity of less than 30micromolar using this test method.

What is claimed is:
 1. A compound which isN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-aminewhich is

or a salt thereof.
 2. A pharmaceutical composition comprising a compoundof claim 1 or a salt thereof and at least one excipient.
 3. The compoundof claim 1 which is a citrate, phosphate or mono- or di-hydrochloridesalt.
 4. The compound of claim 3 which is a citrate salt ofN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine.5. The compound of claim 3 which is a phosphate salt ofN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine.6. The compound of claim 3 which is a mono-hydrochloride salt ofN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine.7. The compound of claim 3 which is a di-hydrochloride salt ofN-{[3,5-difluoro-3′-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine.8. A method of treatment comprising administering a pharmaceuticalcomposition comprising (i) a compound of claim 1 or a salt thereof and(ii) at least one carrier to a human suffering from the condition ofobesity.
 9. A method of treatment comprising administering to a human acompound of claim 1 or a salt thereof, wherein said treatment isobesity.